Vol. 279, Issue 4, F593-F604, October 2000
INVITED REVIEW
MAPK signaling and the kidney
Wei
Tian,
Zheng
Zhang, and
David M.
Cohen
Divisions of Nephrology and Molecular Medicine, Oregon Health
Sciences University, and Portland Veterans Affairs Medical Center,
Portland, Oregon 97201
 |
ABSTRACT |
Following an
overview of the biochemistry of mitogen-activated protein kinase (MAPK)
pathways, the relevance of these signaling events to specific models of
renal cell function and pathophysiology, both in vitro and in vivo,
will be emphasized. In in vitro model systems, events activating the
principal MAPK families [extracellular signal-regulated and c-Jun
NH2-terminal kinase and p38] have been best characterized
in mesangial and tubular epithelial cell culture systems and include
peptide mitogens, cytokines, lipid mediators, and physical stressors.
Several in vivo models of proliferative or toxic renal injury are also
associated with aberrant MAPK regulation. It is anticipated that
elucidation of downstream effector signaling mechanisms and a clearer
understanding of the immediate and remote upstream activating pathways,
when applied to these highly clinically relevant model systems, will
ultimately provide much greater insight into the basis for specificity
now seemingly absent from these signaling events.
urea; tubule; mesangial; extracellular signal-regulated kinase; stress-activated protein kinase; c-Jun NH2-terminal kinase; p38; mitogen-activated protein kinase
| |
INTRODUCTION |
FOLLOWING AN OVERVIEW
of the regulation of mitogen-activated protein kinase (MAPK) signaling,
this review will focus on the relevance of these molecular events to
specific models of renal physiology and pathophysiology, both in vivo
and in vitro.1 As will emerge from this
review, whereas the biochemistry of these pathways is being
defined with increasing precision, their contribution to renal
physiology and pathophysiology remains far less clear. For an in-depth
review of molecular aspects of MAPK signaling, the reader is referred
to any of several recent excellent reviews (23, 42, 124,
149).
| |
MAPKS, MKKS, AND MKKKS |
The core MAPK "module" consists of a MAPK, its upstream
activator [MAPK kinase (MKK)], and a further upstream activator
[MAPK kinase kinase (MKKK); Fig.
1]. MAPKs can be divided into at
least three broad families on the basis of sequence
similarity, upstream activators, and to a lesser extent, substrate
specificity. The classic extracellular signal-regulated kinases (ERKs;
ERK1 and ERK2) were identified in the context of growth factor-related signaling, whereas the jun NH2-terminal kinase (JNK) and
p38 families were described in the setting of cell response to stress
and inflammation. Recently, additional MAPK families have been
identified, of which only ERK5 thus far has clearly delineated upstream
activators and downstream effectors (85, 173).
View larger version (29K):
[in this window]
[in a new window]
|
Fig. 1.
Activators and effectors of the principal
mitogen-activated protein kinase (MAPK) families. Only representative
MAPK effectors (transcription factor substrates) are shown (see text).
Note the relative specificity of the MAPK kinase (MKK) MAPK
activation event for each MAPK module. Arrows, activation events; ?,
unknown activator. ERK, extracellular signal-regulated kinase; MAPK,
mitogen-activated protein kinase; MEK, MAPK/ERK kinase; MEKK, MAPK/ERK
kinase kinase; MKK, MAPK kinase; MKKK, MAPK kinase kinase; PAK,
p21-activated kinase; JNK, c-Jun NH2-terminal kinase; CHOP,
CLAAT/enhancer binding protein (C/EBP) homologous protein; MEF, myocyte
enhancer factor.
|
|
Although the often-quoted paradigm of a discrete physical or
biochemical stimulus (e.g, peptide mitogen, osmotic stress, etc.) resulting in activation of a specific MAPK module has been challenged by recent data, each family of MAPKs is nonetheless activated in a
relatively specific fashion by a subset of MKKs (Fig. 1). For example,
ERK1/2 is activated by both MAPK/ERK kinase (MEK)1 and MEK2 whereas
JNKs are activated primarily by MKK4 and MKK7 and p38 is activated by
MKK3 and MKK6. In contrast, the relationship between individual MKKs
and their upstream MKKKs is less clear. Members of the Raf family
specifically activate the ERK1/2-directed MKKs, MEK1, and MEK2,
although there is considerable crosstalk among the parallel cascades at
the level of MKKKs. Additional MKKK-MKK relationships are detailed in
Fig. 1. A further level of complexity is contributed by the expanding
range of activators of MKKKs (including MKKKKs and small GTP-binding
proteins; reviewed in Ref. 42).
| |
THE ERK PATHWAY |
The ERK1/2 pathway is generally but not exclusively responsive to
activators of both receptor tyrosine kinases and G protein-coupled receptors. Principal mammalian ERKs, p44ERK1 and
p42ERK2, are activated by the MEK1 and MEK2
"dual-specificity" (Ser/Thr and Tyr) kinases that phosphorylate the
TEY motif specific to ERKs. Effectors of activated ERK include
transcription factors [e.g., Elk-1, Ets 1, Sap1a, m-Myc, signal
transducers and activators of transcription proteins (STAT)], adapter
proteins (Sos), enzymes (p90Rsk S6 kinase, phospholipase
A2), and cell surface and nuclear receptors [e.g.,
epidermal growth factor (EGF) and estrogen receptors, respectively]. Elucidation of physiological consequences of
ERK signaling has been enormously facilitated by the availability of
the pharmacological inhibitors of ERK action, PD-98059 (1) and, more recently, U-0126 (39). Both inhibitors appear to
indirectly block ERK signaling through inhibition of its immediate
upstream activators, MEK1 and MEK2. Specificity is not absolute;
PD-98059 is also a potent inhibitor of cyclooxygenase-1 and -2 (15). A recently described highly MEK1-specific derivative
of PD-98059, PD-184352, was functional in vivo, effectively suppressing
tumor growth (128). From a physiological perspective, ERK
signaling has been implicated in mitogenesis and cell differentiation.
In vivo targeted gene disruption ("knockout") of ERK has not been reported, presumably due to embryonic lethality. Targeted gene disruption of the MKKK for the ERK and JNK pathways, MEKK1, enhanced the proapoptotic response to various stressors in embryonic stem cells
(168); targeted disruption of MEKK2 has also been reported (167).
| |
THE JNK/SAPK1 PATHWAY |
The JNK [also known as stress-activated protein kinase-1
(SAPK1)] family members are generally responsive to cell stressors such as hypertonicity, ultraviolet light, heat shock, and
proinflammatory cytokines. Members of this family include the widely
expressed JNK1 (also known as p46 or SAPK1
) and JNK2 (also known as
p54 or SAPK1
), as well as the brain-specific JNK3 (also known as p49
or SAPK1
). JNK1 and JNK2 are subject to alternative splicing, giving
rise to 46- and 54-kDa protein products. To achieve activation, JNKs
undergo MKK-mediated dual phosphorylation at their TPY motifs. Effectors of the JNK family of MAPKs include primarily transcription factors (e.g., c-Jun, Elk-1, ATF-2, DPC4, NFAT4, and p53). Although no
pharamacological inhibitor of the JNK pathway has been widely used, the
activator protein-1 (AP-1) and nuclear factor-
B inhibitor curcumin
(20) and the quinone reductase inhibitors dicoumarol and
menadione (27) specifically blocked JNK activation and
JNK-dependent signaling in diverse contexts through unknown mechanisms.
JNKs in vivo appear to play a role in inflammation, tumorigenesis, and
apoptosis; independent targeted disruption of JNK1, JNK2, and JNK3 have
been reported and are viable (36, 160, 161). Recently, a
JNK1/JNK2 double knockout conferred embryonic lethality and exhibited
dysregulated apoptosis in the central nervous system (90).
Disruption of MKK4, a JNK-directed MKK, also resulted in embryonic
lethality, at least in part, through abnormal hepatogenesis (41,
113, 159).
| |
THE P38/SAPK2 PATHWAY |
The p38 (also known as SAPK2) family includes four isozymes ( through 
), subject to dual phosphorylation at the TGY motif, primarily by the MKKs, MKK3, and MKK6. Members of the p38 family, like
the JNK family, are generally but not exclusively responsive to
environmental stressors. Effectors of the p38 family include both
transcription factors (ATF-2, Elk-1, CHOP/Gadd153, Max, MEF2C) and
enzymes (e.g., MAPKAP kinase). Implication of p38 signaling in cell
physiology was facilitated by the identification of a family of
anti-inflammatory pyridinyl imidazole compounds, including SB-203580
(100), that inhibit most (but not all) p38 isozymes with
high specificity (84). Like PD-98059, however, SB-203580 also inhibits cyclooxygenase-1 and -2, as well as thromboxane synthase
(15). Although targeted disruption of p38 isoforms in vivo
has not been reported, knockout of its immediate upstream activator,
MKK3, exhibited dysregulated cytokine production in vivo (103,
154).
| |
SPECIFICITY IN MAPK SIGNALING CASCADES |
Although crosstalk is evident among parallel MAPK modules,
paradigms are beginning to emerge. Much confusion arose from earlier reliance on overexpression of components of MAPK cascades and in vitro
demonstration of substrate phosphorylation. The greatest degree of
specificity (i.e., least crosstalk) in MAPK signaling now appears to
reside at the level of MKK activation of MAPK (Fig. 1). Substrate
activation by MAPKs, in contrast, is a site of conspicuous crosstalk.
For example, the transcription factor Elk-1 may be activated by members
of each of the three principal MAPK families, whereas other substrates
appear to be activated in a highly MAPK-specific fashion. Upstream
activation events (mediated by MKKKs and recently identified MKKKKs)
comprise another incompletely understood locus of integrative
crosstalk. Additional variables conferring greater specificity to
MAPK-mediated substrate phosphorylation likely include cell
type-specific distribution of MAPK-activating cell surface receptors,
timing and duration of MAPK activation (e.g., 104, 119), involvement of
single vs. multiple MAPK modules, and convergence of other signaling
events on individual MAPK cascades (e.g., 143). In this respect, it is
important to emphasize that physiological stimuli at the organismic
level (e.g., inflammation or hypotension) have numerous biochemical
effectors and that the local end organ-specific consequences of such
stimuli, in terms of posttranslational modification and transcriptional
regulation, will likely represent the net effect of myriad qualitative
and quantitative changes in intracellular signaling inputs.
| |
REGULATION BY COLOCALIZATION |
Although alternative splice products among JNK isoforms have been
noted with interest for several years and represent an attractive candidate for a higher order of MAPK regulation, data in support of
this model are lacking. Evidence supporting other higher orders of MAPK
regulation, in contrast, is mounting. The issue of relative lack of
specificity of MAPK, MKK, and MKKK in vitro catalyzed a search for
proteins that might permit separate elements of a MAPK module to
colocalize in vivo and thereby confer both greater efficiency of
activation and enhanced specificity. Such scaffolding proteins have now
been identified for ERK (123) and JNK (14, 32,
148) in higher eukaryotes, and for the yeast high osmolority glycerol 1 (HOG1) pathway, homologous with the mammalian p38
pathway. MEKK1, a MKKK for the ERK and JNK pathways, may itself
function as a scaffolding protein for MKK4 and JNK (156,
158).
| |
REGULATION BY MAPK-DIRECTED PHOSPHATASE ACTIVITY |
In addition to positive regulation by MKK-mediated
phosphorylation, MAPKs are also subject to negative regulation through dephosphorylation. At least nine distinct dual-specificity
(TXY-directed) phosphatases have been described (55) that
antagonize MKK function. The first characterized in detail, MKP-1 (also
known as hVH1, 3CH143, and CL100), is a nuclear protein and
immediate-early gene product exhibiting equivalent phosphatase activity
against ERK, JNK, and p38 MAPKs (55). Other MAPK-directed
phosphatases, in contrast, exhibit marked substrate specificity; the
phosphatase MKP-3, for example, is most active against phosphorylated
ERK (46, 111). Interestingly, association of MKP-3 with
ERK dramatically enhanced its intrinsic ERK-directed phosphatase
activity (17).
| |
IN VIVO MODELS OF RENAL MAPK ACTIVATION |
Although all three principal MAPKs are expressed in whole kidney
and detectable in various renal cell culture models (see below),
relatively little is known about renal cell type-specific expression
patterns of MAPKs and their activators and effectors in vivo. Terada et
al. (138) showed that ERK1 and ERK2 are expressed in all
nephron segments, as is the MKKK, Raf-1, the MKK, MEK, and the ERK
effector, p90 S6 kinase (Rsk).
In vivo renal model systems have primarily included models of
inflammatory, ischemic, or toxic renal injury, or extreme physiological stress. Two rodent models of proliferative anti-glomerular basement membrane glomerulonephritis were associated with increased renal cortical and glomerular ERK and JNK activation (11). At
least a component of the activated ERK was likely contributed by
infiltrating macrophages on the basis of depletion studies using
total-body X-irradiation (11). Interestingly, these models
were also associated with upregulation of the ERK activator, MEK, at
the mRNA level. A model of primarily mesangial proliferative
glomerulonephritis inducible by anti-thymocyte serum (ATS) was
similarly associated with activation of ERK, p38, and JNK MAPKs in
renal tissue (12, 13, 129). Prednisolone therapy, which
improved proteinuria and glomerular hypercellularity in this model,
also blocked the ATS-mediated increment in ERK and JNK activation
(129). Therapy with heparin similarly abrogated ERK
activation and the concomitant glomerular proliferation
(13). Pretreatment with phosphodiesterase inhibitors known
to interfere with the ERK pathway (105) ameliorated the
clinical severity of ATS-associated renal failure (141), but data with respect to MAPK activation are lacking in this
experimental model. The beneficial effect of phosphodiesterase
inhibitors appeared to be independent of their modest protective effect
on blood pressure (141). The significance of these latter
data with respect to blood pressure are underscored by the recent
observation that subacute glomerular injury induced by salt loading in
the Dahl salt-sensitive rat is associated with chronic activation of
glomerular ERK and JNK (50). In contrast to these animal
models, data addressing the role of MAPK activation in human
proliferative glomerular disease are sparse. In one small series, the
activity of phospholipase A2, an effector of activated
ERKs, was increased in the urine of patients with mesangial
proliferative glomerulonephritis (134).
Rodent models of renal ischemia-reperfusion were associated with renal
JNK (33, 118) and p38 (165), but not ERK
(118), activation, as well as activation (enhanced DNA
binding) of the MAPK-responsive transcription factors, c-Jun and ATF-2
(110). Recently, a potentially novel JNK isoform was
identified in this clinically relevant context (31). The
profile of MAPK activated by ischemia-reperfusion may be somewhat
tissue specific (165). From a therapeutic perspective, the
ischemia-associated activation of JNK may be ameliorated by systemic
administration of the thiol-containing antioxidant
N-acetylcysteine (33).
Toxic renal injury experimentally induced by mercuric chloride
administration, curiously, was associated with two temporal peaks of
renal ERK activation, separated by an interval of relative inactivity
(163). Renal ERK and JNK activation were also increased in
the glycerol model of myoglobinuric acute renal injury
(80). Interestingly, this latter effect was modestly
sensitive to systemic administration of the relatively nonspecific
kinase inhibitor genistein (80).
An increased incidence of ERK activation has been observed in human
renal neoplasia. Oka et al. (114) noted constitutive ERK
activation in fully 48% of renal carcinomata examined
(114). Hoshino et al. (58) detected ERK
activation in tumors derived from diverse tissues; however, a
disproportionate incidence was noted in tumors arising from the kidney.
With respect to physical stressors, exogenously applied heat
stress increased JNK activation in mouse kidney, as well as other (but
not all) tissues (60). Osmotic stress regulates all MAPKs in cell culture models (see below); accordingly, physiological models
of systemic water balance profoundly influence renal medullary MAPK
activation. Water restriction increased ERK, p38, and JNK activity in
renal medullary but not cortical tissue (151, 166). Therefore, despite the markedly elevated medullary tonicity under euvolemic conditions, MAPK activation is submaximal in this unique environment. The relationship between hypertonicity and experimental models of hyperglycemia and diabetes mellitus is often unclear. ERK
activity is increased in glomeruli harvested from diabetic animals;
similarly, exogenous application of elevated glucose to isolated
glomeruli activated ERK (7, 52, 53).
| |
CELL CULTURE MODELS OF MAPK ACTIVATION |
Mesangial Cells
The principal in vitro (cell culture) model systems of renal MAPK
regulation are the mesangial and tubular epithelial cell. Because ERK
activation is often a manifestation of mitogenesis and because
mesangial cell proliferation is a hallmark of numerous glomerular
lesions, intense interest has focused on MAPK regulation in mesangial
cells. Abundant agonists capable of activating MAPKs in cultured
mesangial cells have been described, including peptide mitogens,
cytokines, lipid mediators, and steroid hormones, and physical stimuli
potentially relevant to mesangial function in vivo (Table
1).
ERKs are activated by the peptide mitogen and receptor
tyrosine kinase agonists, platelet-derived growth factor (PDGF)
(22, 67, 73, 125), EGF (125), insulin
(3), and vascular endothelial growth factor (VEGF)
(2), as well as the G protein-coupled-receptor-directed
agonists endothelin (88, 125, 144, 145), ANG II (3,
67), bradykinin (38, 83), lysophosphatidic acid
(40, 73), serotinin (45), and vasopressin (78, 79, 95). The effect of vasopressin on mesangial ERK activation is likely Ras dependent, as evidenced by its sensitivity to
the hydroxymethylglutaryl-CoA inhibitor (and, therefore, prenylation inhibitor) simvastatin (78). The effect of
lysophosphatidic acid in this model likely requires activation of the
PDGF receptor (44). Activation of the G protein-coupled
purinergic receptor by nucleotide triphosphates also induces ERK
activation (65, 76) and is sensitive to the antioxidant
N-acetylcysteine (65). In addition to ERK,
several agonists of G protein-coupled receptors also activate JNK in
mesangial cells, including ANG II (69), endothelin
(4), and nucleotide triphosphates (70).
As in other models, proinflammatory cytokines such as tumor necrosis
factor- (49) and interleukin-1 (IL-1) (63,
134, 142, 150) activate various MAPKs in glomerular mesangial
cells in culture, an effect that may be dependent on the generation of
oxidative stress (150). Activation of JNK in this context may also require arachidonic acid release (61), whereas
activation of both p38 and JNK appears to mediate the ability of
inflammatory cytokines to upregulate expression of cyclooxygenase-2
(47). Similarly, p38 and/or JNK activation is likely
required for IL-1-inducible chemoattractant protein-1
(122) and nitric oxide synthase expression (48). The cytokine transforming growth factor-2 also
activates ERK in mesangial cells (66), whereas nitric
oxide activates all three MAPK families (16, 64, 117).
The lipid mediators lysophosphatidic acid (40, 73) and
sphingosine (26) as well as selected lipoproteins
(8, 109) all induce ERK activation in cultured mesangial
cells. In addition, ERK and p38 appear to play a role in gene
regulation downstream of lysophosphatidic acid signaling
(120) in this model. Interestingly, whereas the lipid
mediator ceramide activates JNK but not ERK, the ceramide metabolite
sphingosine specifically activates ERK but not JNK (26).
Correspondingly, ceramide generation has been implicated in cytokine
signaling and sphingosine production in the growth factor response.
Low-density lipoprotein can potentiate the effect of vasopressin on ERK
activation (77). Exogenous application of soluble
phospholipase A2, catalyzing the enzymatic release of free
arachidonic acid from biological membranes, activated ERK in mesangial
cells (68, 134). Phospholipase A2 is also activated by ERK, suggesting the interesting scenario of cyclic potentiation of ERK signaling in this specific context.
Physical stimuli such as hyperglycemia (43, 52-54,
56), cyclic two-dimensional mechanical stretch and relaxation
(72, 74), and collagen gel three-dimensional contraction
(169) all activate ERK in mesangial cells. Elevated
hydrostatic pressure is particularly relevant to the mesangium in vivo;
an in vitro model achieved by using an air pressure loading apparatus
(to 70 mmHg) resulted in enhanced mesangial cell ERK activation and proliferation (86). A measure of specificity in these
events is implied by the inability of elevated pressure to activate JNK (86), and the additional ability of mechanical strain to
activate p38 but not JNK (72). Cadmium induces ERK
activation (136, 146), but it is unclear whether this
represents a heavy metal (toxic) or oxidative stress-dependent effect.
In addition to activators, several stimuli functionally antagonize MAPK
signaling in the mesangial cell model. With respect to ERK signaling,
vasodilatory mediators such as prostaglandin analogs (71,
102), dopamine (164), atrial natriuretic peptide (51, 133), and adrenomedullin (21, 116) all
block ERK activation in various contexts, as do heparin
(108), high glucose (106), phosphodiesterase
inhibitors (105), and cAMP and cGMP analogs (51,
132). A number of these inhibitory events appear to be mediated
through the action of cyclic nucleotide monophosphate (e.g., cAMP and
cGMP) second-messenger systems.
In addition to regulating activation of MAPKs, several stimuli may
directly regulate abundance of MAPK cascade consituents. For example,
in addition to increasing ERK activity, transforming growth factor-2
(66), IL-1 (63), endothelin-1 (126,
127), PDGF (126, 127), and fetal bovine serum
(126) also increased the abundance of mRNA coding for the
ERK activator MEK in mesangial cells. Similarly, in addition to
activating ERK, PDGF stimulates ERK synthesis (62). A
prostacyclin analog increases expression of the ERK-directed
phosphatase MKP-1 and thereby potentially antagonizes MAPK signaling in
the mesangium (140).
Renal Tubular Epithelial Cells
A subset of renal epithelial cells lining the distal nephron are
subjected to an elevated and, at times, rapidly fluctuating ambient
osmolarity as a consequence of the renal concentrating mechanism. In
light of earlier descriptions of activation of each of the three
prinicpal MAPK families by hypertonic stress, the renal epithelial cell
(and particularly, renal medullary cell) model provided an ideal
physiological context in which to explore this phenomenon. Several
recent reviews (92, 98) address this theme in greater
detail. As in other (nonrenal) models, application of hypertonicity to
renal epithelial cells in culture activates ERK (82, 137),
p38 (10, 147, 170), and JNK (10, 170) (See
Table 2). Hypotonicity also increases activation of ERK and JNK in this
model (172), events that partially explain the ability of
this stimulus to activate immediate-early gene expression. Although
pharmacological inhibition of the ERK pathway affected cell volume
regulation, it did not appear to influence cell viability in the
setting of hypotonicity (172). The role of each of these kinases in gene regulation by hypertonicity is less clear. Kwon et al.
(96) reported that ERK activation in Madin-Darby canine kidney (MDCK) cells was dispensible for osmotic induction of genes encoding osmolyte transporters (96). Kultz et al.
(93) reported that, in the renal medullary mIMCD3 cell
line, tonicity-inducible transcription directed by the osmotic or
tonicity-responsive DNA enhancer element was similarly independent of
p38 activation and that heterologous overexpression of dominant
negative MKK3 and MKK4 isoforms failed to influence osmotic gene
induction. Sheikh-Hamad et al. (130), in sharp contrast,
observed that pharmacological inhibition of p38 action blocked
hypertonicity-inducible transcription of genes encoding both the heat
shock protein HSP70 and osmolyte transporters. In terms of cell volume
regulation, p38 activation likely mediates a component of the
regulatory volume increase response in cells of the medullary thick
limb (121). Activation of p38 has also been reputed to
mediate, in part, the ability of hypertonicity to increase expression
of the stress-responsive protein products of the GADD45 and GADD153
genes (94). With respect to the JNK pathway, Wojtaszek et
al. (152) observed that hypertonicity activated JNK2 but
not JNK1 in the mIMCD3 model; more importantly, inhibition of the JNK2
pathway through a dominant negative approach sensitized cells to the
proapoptotic effect of hypertonicity. In addition to regulating MAPK
activation, anisotonicity also influences abundance of a MAPK
antagonist. Specifically, expression of the ERK-directed phosphatase
MKP-1 is responsive to ambient tonicity in the MDCK model
(81), affording an additional level of complexity.
Similar in some respects to hypertonic stress is the unique medullary
stress engendered by urea. Urea, in concentrations unique to the renal
medulla, activates primarily the ERK MAPKs (10, 24, 170)
in inner medullary collecting duct cells, although modest activation of
JNK and p38 has also been observed in this model (10,
162). Urea-inducible ERK activation, a partially Ras-dependent
phenomenon (139), results in activation of the translational regulatory kinase p90Rsk (171)
and underlies, in part, the ability of this stimulus to regulate
immediate-early gene transcription (24). The medullary cell response to urea is distinct from that of hypertonicity in a
number of respects, and is in large part cell volume independent (162)
As in other models, receptor agonists regulate activation of MAPK
family members in renal tubular epithelial cells. With respect to
receptor tyrosine kinase activators, EGF activated ERK in IMCD and OMCD
cells (57, 138). Hepatocyte growth factor activated ERK in
the MDCK cell line (135), a signaling event implicated in
hepatocyte growth factor-inducible epithelial cell scatter (135). With respect to G protein-coupled receptor
agonists, bradykinin activated ERK in cortical collecting duct cells
(97), purinergic agonists (NTPs) activated ERK in MDCK and
inner medullary collecting duct (IMCD)/T cells (57, 75,
155), ANG II activated ERK in opossum kidney (OK) proximal
tubule-like and IMCD cells (137), epinephrine activated
ERK in MDCK cells (155), endothelin activated ERK in IMCD
and outer medullary collecting duct cells (138), G1-2 activated ERK in LLC-PK1 cells
(87), and carbachol activated ERK in inner medullary
collecting tubule cells (57). Bradykinin induces
arachidonic acid release via ERK activation (97), an event
potentially attributable to downstream activation of phospholipase
A2. Other ERK activators in renal epithelial models include
lactosylceramide, a lipid mediator increased in polycystic kidney
disease tissue that increased ERK activity in human tubular epithelial
cells (18); arachidonic acid, which increased ERK activity
in rabbit proximal tubule cells (37); epoxyeicosatrienoic
acid, lipid signaling intermediates that increased ERK activity in
LLC-PKc14 cells (19); advanced glycation
end-products, nonenzymatically modified macromolecules associated with
hyperglycemia and diabetes mellitus that increased ERK activity in
LLC-PK1 cells (131); and ATP depletion, which
also activated ERK in the LLC-PK1 model (110).
Only very limited data describe nonosmotic regulation of MAPKs other
than ERKs in renal tubular epithelial models. The heavy metal and
oxidative stressor cadmium activated JNK in LLC-PK1 cells
(107), consistent with data in other models. JNK was also activated in rabbit proximal tubule cells in response to arachidonic acid treatment, an effect dependent on NADPH oxidase activity (28).
Antagonists of MAPK (specifically, ERK) in renal epithelial cells, as
in mesangial cells, likely function in a cAMP-dependent fashion. For
example, vasopressin inhibited EGF-inducible ERK activation in MDCK
cells (157). Nonenzymatically glycated extracellular matrix, accompanying diabetes mellitus in vivo, also has been shown to
block activation of ERK (89), in marked contrast to the
effect of exogenously applied advanced glycation end-products described
above (131). Also of note with respect to renal
pathophysiology, the protein product of the VHL locus, implicated in
renal carcinoma development, appears to interfere with ERK activation
(115). The relationship between this biochemical finding
and the pathogenesis of neoplasia remains speculative, however.
Other Glomerular Cell Types
In contrast to mesangial cells and renal tubular epithelial cell
types, less is known about MAPK regulation in other resident renal
cells. In glomerular epithelial cells, the likely origin for crescent
formation in inflammatory glomerulopathies, exogenous application of
complement-activated ERK and the ERK effector phospholipase A2 but not p38 (30). ERK activation in this
model may also be modulated in part by matrix composition
(29). In glomerular endothelial cells, in direct contact
with the intraglomerular bloodspace in vivo, the vasoactive mediators
ANG II and nitric oxide activated both ERK (153) and JNK
(117), respectively. Although performed in the relatively
poorly differentiated human embryonal HEK-293 kidney cell line, recent
studies addressing signaling events engendered by the protein products
of the polycystic kidney disease loci are of great interest.
Specifically, heterologous overexpression of PKD1 resulted in
activation of JNK but not ERK or p38 (5) and further led
to enhanced AP-1-dependent (i.e., immediate-early gene) transcription.
In contrast, heterologous overexpression of PKD2 resulted in activation
of both JNK and p38. Like overexpression of PKD1, PKD2 expression was
associated with enhanced AP-1-dependent transcription (6);
however, coexpression of these protein products markedly augmented
signaling to AP-1-dependent transcription.
| |
SUMMARY AND FUTURE DIRECTIONS |
In renal cells in culture, a broad range of biochemical,
pharmacological, and even physical stimuli all converge on activation of elements of one or more of the MAPK families. Comparatively few such
events have been observed in in vivo models of renal pathophysiology;
far fewer still have been directly implicated in human renal disease,
owing in large part to the paucity of clinical material and the extreme
lability of the activation (phosphorylation) events under
investigation. It is anticipated that elucidation of downstream
effector signaling mechanisms and a clearer understanding of immediate
and remote upstream activating pathways, when applied to these
disparate but highly clinically relevant renal cell culture model
systems, will ultimately provide much greater insight into the basis
for specificity now seemingly absent from these signaling events. An
appreciation of this specificity, or lack thereof, is a prerequisite
for the intelligent application of pharmacological interventions aimed
at disrupting or potentiating these signaling pathways in combating
human disease.
| |
ACKNOWLEDGEMENTS |
This work was supported by National Institute of Diabetes and
Digestive and Kidney Diseases Grant DK-52494 and by the American Heart Association.
| |
FOOTNOTES |
Address for reprint requests and other correspondence: D. M. Cohen, Oregon Health Sciences Univ., Portland, OR 97201 (E-mail:cohend{at}ohsu.edu).
1
The following search algorithm (PubMed) was used
(through 2/00): (ERK OR extracellular-signal OR MAPK OR
mitogen-activated OR SAPK OR stress-activated OR JNK OR c-jun
NH2-terminal OR jun N-terminal OR p38 OR HOG1) AND (renal
OR kidney OR nephron OR glomerular OR glomerulus OR mesangial OR mesangium).
| |
REFERENCES |
1.
Alessi, DR,
Cuenda A,
Cohen P,
Dudley DT,
and
Saltiel AR.
PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo.
J Biol Chem
270:
27489-27494,
1995[Abstract/Free Full Text].
2.
Amemiya, T,
Sasamura H,
Mifune M,
Kitamura Y,
Hirahashi J,
Hayashi M,
and
Saruta T.
Vascular endothelial growth factor activates MAP kinase and enhances collagen synthesis in human mesangial cells.
Kidney Int
56:
2055-2063,
1999[ISI][Medline].
3.
Anderson, PW,
Zhang XY,
Tian J,
Correale JD,
Xi XP,
Yang D,
Graf K,
Law RE,
and
Hsueh WA.
Insulin and angiotensin II are additive in stimulating TGF-1 and matrix mRNAs in mesangial cells.
Kidney Int
50:
745-753,
1996[ISI][Medline].
4.
Araki, S,
Haneda M,
Togawa M,
and
Kikkawa R.
Endothelin-1 activates c-Jun NH2-terminal kinase in mesangial cells.
Kidney Int
51:
631-639,
1997[ISI][Medline].
5.
Arnould, T,
Kim E,
Tsiokas L,
Jochimsen F,
Gruning W,
Chang JD,
and
Walz G.
The polycystic kidney disease 1 gene product mediates protein kinase C -dependent and c-Jun N-terminal kinase-dependent activation of the transcription factor AP-1.
J Biol Chem
273:
6013-6018,
1998[Abstract/Free Full Text].
6.
Arnould, T,
Sellin L,
Benzing T,
Tsiokas L,
Cohen HT,
Kim E,
and
Walz G.
Cellular activation triggered by the autosomal dominant polycystic kidney disease gene product PKD2.
Mol Cell Biol
19:
3423-3434,
1999[Abstract/Free Full Text].
7.
Awazu, M,
Ishikura K,
Hida M,
and
Hoshiya M.
Mechanisms of mitogen-activated protein kinase activation in experimental diabetes.
J Am Soc Nephrol
10:
738-745,
1999[Abstract/Free Full Text].
8.
Bassa, BV,
Roh DD,
Kirschenbaum MA,
and
Kamanna VS.
Atherogenic lipoproteins stimulate mesangial cell p42 mitogen-activated protein kinase.
J Am Soc Nephrol
9:
488-496,
1998[Abstract].
9.
Bassa, BV,
Roh DD,
Vaziri ND,
Kirschenbaum MA,
and
Kamanna VS.
Lysophosphatidylcholine activates mesangial cell PKC and MAP kinase by PLC-1 and tyrosine kinase-Ras pathways.
Am J Physiol Renal Physiol
277:
F328-F337,
1999[Abstract/Free Full Text].
10.
Berl, T,
Siriwardana G,
Ao L,
Butterfield LM,
and
Heasley LE.
Multiple mitogen-activated protein kinases are regulated by hyperosmolality in mouse IMCD cells.
Am J Physiol Renal Physiol
272:
F305-F311,
1997[Abstract/Free Full Text].
11.
Bokemeyer, D,
Guglielmi KE,
McGinty A,
Sorokin A,
Lianos EA,
and
Dunn MJ.
Activation of extracellular signal-regulated kinase in proliferative glomerulonephritis in rats.
J Clin Invest
100:
582-588,
1997[ISI][Medline].
12.
Bokemeyer, D,
Guglielmi KE,
McGinty A,
Sorokin A,
Lianos EA,
and
Dunn MJ.
Different activation of mitogen-activated protein kinases in experimental proliferative glomerulonephritis.
Kidney Int Suppl
67:
S189-S191,
1998[Medline].
13.
Bokemeyer, D,
Ostendorf T,
Kunter U,
Lindemann M,
Kramer HJ,
and
Floege J.
Differential activation of mitogen-activated protein kinases in experimental mesangioproliferative glomerulonephritis.
J Am Soc Nephrol
11:
232-240,
2000[Abstract/Free Full Text].
14.
Bonny, C,
Nicod P,
and
Waeber G.
IB1, a JIP-1-related nuclear protein present in insulin-secreting cells.
J Biol Chem
273:
1843-1846,
1998[Abstract/Free Full Text].
15.
Borsch-Haubold, AG,
Pasquet S,
and
Watson SP.
Direct inhibition of cyclooxygenase-1 and -2 by the kinase inhibitors SB 203580 and PD 98059. SB 203580 also inhibits thromboxane synthase.
J Biol Chem
273:
28766-28772,
1998[Abstract/Free Full Text].
16.
Callsen, D,
Pfeilschifter J,
and
Brune B.
Rapid and delayed p42/p44 mitogen-activated protein kinase activation by nitric oxide: the role of cyclic GMP and tyrosine phosphatase inhibition.
J Immunol
161:
4852-4858,
1998[Abstract/Free Full Text].
17.
Camps, M,
Nichols A,
Gillieron C,
Antonsson B,
Muda M,
Chabert C,
Boschert U,
and
Arkinstall S.
Catalytic activation of the phosphatase MKP-3 by ERK2 mitogen-activated protein kinase.
Science
280:
1262-1265,
1998[Abstract/Free Full Text].
18.
Chatterjee, S,
Shi WY,
Wilson P,
and
Mazumdar A.
Role of lactosylceramide and MAP kinase in the proliferation of proximal tubular cells in human polycystic kidney disease.
J Lipid Res
37:
1334-1344,
1996[Abstract].
19.
Chen, JK,
Falck JR,
Reddy KM,
Capdevila J,
and
Harris RC.
Epoxyeicosatrienoic acids and their sulfonimide derivatives stimulate tyrosine phosphorylation and induce mitogenesis in renal epithelial cells.
J Biol Chem
273:
29254-29261,
1998[Abstract/Free Full Text].
20.
Chen, YR,
and
Tan TH.
Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway by curcumin.
Oncogene
17:
173-178,
1998[ISI][Medline].
21.
Chini, EN,
Choi E,
Grande JP,
Burnett JC,
and
Dousa TP.
Adrenomedullin suppresses mitogenesis in rat mesangial cells via cAMP pathway.
Biochem Biophys Res Commun
215:
868-873,
1995[ISI][Medline].
22.
Choudhury, GG,
Karamitsos C,
Hernandez J,
Gentilini A,
Bardgette J,
and
Abboud HE.
PI-3-kinase and MAPK regulate mesangial cell proliferation and migration in response to PDGF.
Am J Physiol Renal Physiol
273:
F931-F938,
1997.
23.
Cobb, MH.
MAP kinase pathways.
Prog Biophys Mol Biol
71:
479-500,
1999[ISI][Medline].
24.
Cohen, DM.
Urea-inducible Egr-1 transcription in renal inner medullary collecting duct (mIMCD3) cells is mediated by extracellular signal-regulated kinase activation.
Proc Natl Acad Sci USA
93:
11242-11247,
1996[Abstract/Free Full Text].
25.
Cole, JA.
Parathyroid hormone activates mitogen-activated protein kinase in opossum kidney cells.
Endocrinology
140:
5771-5779,
1999[Abstract/Free Full Text].
26.
Coroneos, E,
Wang Y,
Panuska JR,
Templeton DJ,
and
Kester M.
Sphingolipid metabolites differentially regulate extracellular signal-regulated kinase and stress-activated protein kinase cascades.
Biochem J
316:
13-17,
1996.
27.
Cross, JV,
Deak JC,
Rich EA,
Qian Y,
Lewis M,
Parrott LA,
Mochida K,
Gustafson D,
Vande Pol S,
and
Templeton DJ.
Quinone reductase inhibitors block SAPK/JNK and NFB pathways and potentiate apoptosis.
J Biol Chem
274:
31150-31154,
1999[Abstract/Free Full Text].
28.
Cui, XL,
and
Douglas JG.
Arachidonic acid activates c-jun N-terminal kinase through NADPH oxidase in rabbit proximal tubular epithelial cells.
Proc Natl Acad Sci USA
94:
3771-3776,
1997[Abstract/Free Full Text].
29.
Cybulsky, AV,
and
McTavish AJ.
Extracellular matrix is required for MAP kinase activation and proliferation of rat glomerular epithelial cells.
Biochem Biophys Res Commun
231:
160-166,
1997[ISI][Medline].
30.
Cybulsky, AV,
Papillon J,
and
McTavish AJ.
Complement activates phospholipases and protein kinases in glomerular epithelial cells.
Kidney Int
54:
360-372,
1998[ISI][Medline].
31.
De Silva, H,
Cioffi C,
Yin T,
Sandhu G,
Webb RL,
and
Whelan J.
Identification of a novel stress activated kinase in kidney and heart.
Biochem Biophys Res Commun
250:
647-652,
1998[ISI][Medline].
32.
Dickens, M,
Rogers JS,
Cavanagh J,
Raitano A,
Xia Z,
Halpern JR,
Greenberg ME,
Sawyers CL,
and
Davis RJ.
A cytoplasmic inhibitor of the JNK signal transduction pathway.
Science
277:
693-696,
1997[Abstract/Free Full Text].
33.
DiMari, J,
Megyesi J,
Udvarhelyi N,
Price P,
Davis R,
and
Safirstein R.
N-acetyl cysteine ameliorates ischemic renal failure.
Am J Physiol Renal Physiol
272:
F292-F298,
1997[Abstract/Free Full Text].
34.
Dixon, R,
and
Brunskill NJ.
Albumin stimulates p44/p42 extracellular-signal-regulated mitogen-activated protein kinase in opossum kidney proximal tubular cells.
Clin Sci (Colch)
98:
295-301,
2000[Medline].
35.
Dixon, RJ,
and
Brunskill NJ.
Lysophosphatidic acid-induced proliferation in opossum kidney proximal tubular cells: role of PI 3-kinase and ERK.
Kidney Int
56:
2064-2075,
1999[ISI][Medline].
36.
Dong, C,
Yang DD,
Wysk M,
Whitmarsh AJ,
Davis RJ,
and
Flavell RA.
Defective T cell differentiation in the absence of Jnk1.
Science
282:
2092-2095,
1998[Abstract/Free Full Text].
37.
Dulin, NO,
Sorokin A,
and
Douglas JG.
Arachidonate-induced tyrosine phosphorylation of epidermal growth factor receptor and Shc-Grb2-Sos association.
Hypertension
32:
1089-1093,
1998[Abstract/Free Full Text].
38.
El-Dahr, SS,
Dipp S,
and
Baricos WH.
Bradykinin stimulates the ERKElk-1Fos/AP-1 pathway in mesangial cells.
Am J Physiol Renal Physiol
275:
F343-F352,
1998[Abstract/Free Full Text].
39.
Favata, MF,
Horiuchi KY,
Manos EJ,
Daulerio AJ,
Stradley DA,
Feeser WS,
Van Dyk DE,
Pitts WJ,
Earl RA,
Hobbs F,
Copeland RA,
Magolda RL,
Scherle PA,
and
Trzaskos JM.
Identification of a novel inhibitor of mitogen-activated protein kinase kinase.
J Biol Chem
273:
18623-18632,
1998[Abstract/Free Full Text].
40.
Gaits, F,
Salles JP,
and
Chap H.
Dual effect of lysophosphatidic acid on proliferation of glomerular mesangial cells.
Kidney Int
51:
1022-1027,
1997[ISI][Medline].
41.
Ganiatsas, S,
Kwee L,
Fujiwara Y,
Perkins A,
Ikeda T,
Labow MA,
and
Zon LI.
SEK1 deficiency reveals mitogen-activated protein kinase cascade crossregulation and leads to abnormal hepatogenesis.
Proc Natl Acad Sci USA
95:
6881-6886,
1998[Abstract/Free Full Text].
42.
Garrington, TP,
and
Johnson GL.
Organization and regulation of mitogen-activated protein kinase signaling pathways.
Curr Opin Cell Biol
11:
211-218,
1999[ISI][Medline].
43.
Glogowski, EA,
Tsiani E,
Zhou X,
Fantus IG,
and
Whiteside C.
High glucose alters the response of mesangial cell protein kinase C isoforms to endothelin-1.
Kidney Int
55:
486-499,
1999[ISI][Medline].
44.
Goppelt-Struebe, M,
Fickel S,
and
Reiser CO.
The platelet-derived-growth-factor receptor, not the epidermal-growth- factor receptor, is used by lysophosphatidic acid to activate p42/44 mitogen-activated protein kinase and to induce prostaglandin G/H synthase-2 in mesangial cells.
Biochem J
345:
217-224,
2000.
45.
Grewal, JS,
Mukhin YV,
Garnovskaya MN,
Raymond JR,
and
Greene EL.
Serotonin 5-HT2A receptor induces TGF-1 expression in mesangial cells via ERK: proliferative and fibrotic signals.
Am J Physiol Renal Physiol
276:
F922-F930,
1999[Abstract/Free Full Text].
46.
Groom, LA,
Sneddon AA,
Alessi DR,
Dowd S,
and
Keyse SM.
Differential regulation of the MAP, SAP and RK/p38 kinases by Pyst1, a novel cytosolic dual-specificity phosphatase.
Embo J
15:
3621-3632,
1996[ISI][Medline].
47.
Guan, Z,
Buckman SY,
Miller BW,
Springer LD,
and
Morrison AR.
Interleukin-1-induced cyclooxygenase-2 expression requires activation of both c-Jun NH2-terminal kinase and p38 MAPK signal pathways in rat renal mesangial cells.
J Biol Chem
273:
28670-28676,
1998[Abstract/Free Full Text].
48.
Guan, Z,
Buckman SY,
Springer LD,
and
Morrison AR.
Both p38(MAPK) and JNK/SAPK pathways are important for induction of nitric-oxide synthase by interleukin-1 in rat glomerular mesangial cells.
J Biol Chem
274:
36200-36206,
1999[Abstract/Free Full Text].
49.
Guo, YL,
Baysal K,
Kang B,
Yang LJ,
and
Williamson JR.
Correlation between sustained c-Jun N-terminal protein kinase activation and apoptosis induced by tumor necrosis factor- in rat mesangial cells.
J Biol Chem
273:
4027-4034,
1998[Abstract/Free Full Text].
50.
Hamaguchi, A,
Kim S,
Yano M,
Yamanaka S,
and
Iwao H.
Activation of glomerular mitogen-activated protein kinases in angiotensin II-mediated hypertension.
J Am Soc Nephrol
9:
372-380,
1998[Abstract].
51.
Haneda, M,
Araki S,
Sugimoto T,
Togawa M,
Koya D,
and
Kikkawa R.
Differential inhibition of mesangial MAP kinase cascade by cyclic nucleotides.
Kidney Int
50:
384-391,
1996[ISI][Medline].
52.
Haneda, M,
Araki S,
Togawa M,
Sugimoto T,
Isono M,
and
Kikkawa R.
Activation of mitogen-activated protein kinase cascade in diabetic glomeruli and mesangial cells cultured under high glucose conditions.
Kidney Int Suppl
60:
S66-S69,
1997[Medline].
53.
Haneda, M,
Araki S,
Togawa M,
Sugimoto T,
Isono M,
and
Kikkawa R.
Mitogen-activated protein kinase cascade is activated in glomeruli of diabetic rats and glomerular mesangial cells cultured under high glucose conditions.
Diabetes
46:
847-853,
1997[Abstract].
54.
Haneda, M,
Kikkawa R,
Sugimoto T,
Koya D,
Araki S,
Togawa M,
and
Shigeta Y.
Abnormalities in protein kinase C and MAP kinase cascade in mesangial cells cultured under high glucose conditions.
J Diabetes Complications
9:
246-248,
1995[ISI][Medline].
55.
Haneda, M,
Sugimoto T,
and
Kikkawa R.
Mitogen-activated protein kinase phosphatase: a negative regulator of the mitogen-activated protein kinase cascade.
Eur J Pharmacol
365:
1-7,
1999[ISI][Medline].
56.
Hayama, M,
Akiba S,
Fukuzumi M,
and
Sato T.
High glucose-induced cytosolic phospholipase A2 activation responsible for eicosanoid production in rat mesangial cells.
J Biochem (Tokyo)
122:
1196-1201,
1997[Abstract/Free Full Text].
57.
Heasley, LE,
Senkfor SI,
Winitz S,
Strasheim A,
Teitelbaum I,
and
Berl T.
Hormonal regulation of MAP kinase in cultured rat inner medullary collecting tubule cells.
Am J Physiol Renal Fluid Electrolyte Physiol
267:
F366-F373,
1994[Abstract/Free Full Text].
58.
Hoshino, R,
Chatani Y,
Yamori T,
Tsuruo T,
Oka H,
Yoshida O,
Shimada Y,
Ari-i S,
Wada H,
Fujimoto J,
and
Kohno M.
Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors.
Oncogene
18:
813-22,
1999[ISI][Medline].
59.
Hu, MC,
Wang YP,
Mikhail A,
Qiu WR,
and
Tan TH.
Murine p38-delta mitogen-activated protein kinase, a developmentally regulated protein kinase that is activated by stress and proinflammatory cytokines.
J Biol Chem
274:
7095-8102,
1999[Abstract/Free Full Text].
60.
Hu, Y,
Metzler B,
and
Xu Q.
Discordant activation of stress-activated protein kinases or c-Jun NH2-terminal protein kinases in tissues of heat-stressed mice.
J Biol Chem
272:
9113-9119,
1997[Abstract/Free Full Text].
61.
Huang, S,
Konieczkowski M,
Schelling JR,
and
Sedor JR.
Interleukin-1 stimulates Jun N-terminal/stress-activated protein kinase by an arachidonate-dependent mechanism in mesangial cells.
Kidney Int
55:
1740-1749,
1999[ISI][Medline].
62.
Huwiler, A,
Fabbro D,
and
Pfeilschifter J.
Platelet-derived growth factor stimulates de-novo synthesis of mitogen-activated protein kinase in renal mesangial cells.
Eur J Biochem
227:
209-213,
1995[ISI][Medline].
63.
Huwiler, A,
and
Pfeilschifter J.
Interleukin-1 stimulates de novo synthesis of mitogen-activated protein kinase in glomerular mesangial cells.
FEBS Lett
350:
135-138,
1994[ISI][Medline].
64.
Huwiler, A,
and
Pfeilschifter J.
Nitric oxide stimulates the stress-activated protein kinase p38 in rat renal mesangial cells.
J Exp Biol
202:
655-660,
1999[Abstract].
65.
Huwiler, A,
and
Pfeilschifter J.
Stimulation by extracellular ATP and UTP of the mitogen-activated protein kinase cascade and proliferation of rat renal mesangial cells.
Br J Pharmacol
113:
1455-1463,
1994[ISI][Medline].
66.
Huwiler, A,
and
Pfeilschifter J.
Transforming growth factor 2 stimulates acute and chronic activation of the mitogen-activated protein kinase cascade in rat renal mesangial cells.
FEBS Lett
354:
255-258,
1994[ISI][Medline].
67.
Huwiler, A,
Stabel S,
Fabbro D,
and
Pfeilschifter J.
Platelet-derived growth factor and angiotensin II stimulate the mitogen-activated protein kinase cascade in renal mesangial cells: comparison of hypertrophic and hyperplastic agonists.
Biochem J
305:
777-784,
1995.
68.
Huwiler, A,
Staudt G,
Kramer RM,
and
Pfeilschifter J.
Cross-talk between secretory phospholipase A2 and cytosolic phospholipase A2 in rat renal mesangial cells.
Biochim Biophys Acta
1348:
257-272,
1997[Medline].
69.
Huwiler, A,
van Rossum G,
Wartmann M,
and
Pfeilschifter J.
Angiotensin II stimulation of the stress-activated protein kinases in renal mesangial cells is mediated by the angiotensin AT1 receptor subtype.
Eur J Pharmacol
343:
297-302,
1998[ISI][Medline].
70.
Huwiler, A,
van Rossum G,
Wartmann M,
and
Pfeilschifter J.
Stimulation by extracellular ATP and UTP of the stress-activated protein kinase cascade in rat renal mesangial cells.
Br J Pharmacol
120:
807-812,
1997[ISI][Medline].
71.
Ikeda, M,
Ikeda U,
Shimada K,
Fujita N,
Okada K,
Saito T,
Minota S,
and
Kano S.
Tranilast inhibits the growth of rat mesangial cells.
Eur J Pharmacol
324:
283-287,
1997[ISI][Medline].
72.
Ingram, AJ,
Ly H,
Thai K,
Kang M,
and
Scholey JW.
Activation of mesangial cell signaling cascades in response to mechanical strain.
Kidney Int
55:
476-485,
1999[ISI][Medline].
73.
TOP
ABSTRACT
INTRODUCTION
