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Departments of 1Pathology and Laboratory Medicine, 3Cardiology, 4Surgery, and 5Internal Medicine, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands; and 2Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
Submitted 24 May 2006 ; accepted in final form 1 August 2006
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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-smooth muscle actin, and collagen III expression and with tubulointerstitial fibrosis. Damaged tubular segments expressing activated p38 also expressed Kim-1. Urinary Kim-1 was increased in Ren2 vs. SD (458 ± 70 vs. 27 ± 2 pg/ml, P < 0.01) rats and abolished in Ren2 rats treated with ramipril (33 ± 5 pg/ml, P < 0.01). Kim-1 is associated with development of RAS-mediated renal damage. Antifibrotic treatment through RAS blockade or p38 MAP kinase inhibition reduced Kim-1 in the homozygous Ren2 model. homozygous TGR(mRen2)27; angiotensin II type 1 receptor
Various animal models have been developed to study effects of RAS-mediated renal damage. The homozygous Ren2 model is characterized by overexpression of a mouse renin transgene (Ren2) (11). Previous studies have demonstrated the presence of tubulointerstitial changes indicating prefibrotic damage in this model (9). In homozygous Ren2 rats we recently showed an increase in interstitial -smooth muscle actin (SMA) expression that could be reduced by AT1 receptor blockade or inhibition of MAP kinases that are involved in ANG II-mediated signaling (2). Since the pathophysiology of tubulointerstitial injury in RAS-mediated renal damage is incompletely elucidated, it is important to further identify factors associated with tubulointerstitial damage in the Ren2 model.
Kidney injury molecule-1 (Kim-1) is an epithelial cell adhesion molecule that is induced in damaged tubular epithelial cells undergoing dedifferentiation and replication (7). Although Kim-1 was originally described to be induced in the postischemic kidney, tubular Kim-1 induction has also been reported recently in animal models of toxic (8) and proteinuric (22) renal disease and in polycystic kidney disease (10). Moreover, in human renal biopsies, Kim-1 is expressed in renal carcinoma cells and tubular epithelial cells adjacent to carcinoma cells, i.e., cells that may be subjected to compression by tumor cells or in an early phase of tumorigenesis (4). Kim-1 can also be shed into the urine; urinary Kim-1 concentration correlates with the severity of renal damage (21). Preliminary in vitro studies suggest that shedding of the Kim-1 ectodomain is potentiated by p38 MAP kinase (24). Together, these findings indicate that Kim-1 is expressed in dedifferentiating tubular epithelial cells and, therefore, may play an important role in early tubular damage by modulation of damage or repair mechanisms. Although induction of Kim-1 in renal damage is apparent, its actual function and mechanisms of activation are unclear. Moreover, it is not known whether renoprotective interventions can reduce Kim-1 expression.
To investigate whether Kim-1 is involved in RAS-mediated renal damage, we studied its expression and its association with markers of prefibrotic tubulointerstitial damage in homozygous Ren2 rats. Furthermore, we investigated whether RAS blockade or p38 MAP kinase inhibition, known antifibrotic interventions in the Ren2 model, would affect Kim-1 expression.
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MATERIALS AND METHODS |
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At 7 wk of age, Ren2 animals were divided into three groups (n = 7) and left untreated or treated for 4 wk with a nonhypotensive dose of the AT1 receptor antagonist (AT1RA) candesartan or the p38 MAP kinase inhibitor SB-239063 (see below). Untreated SD rats served as negative controls (n = 7).
The animals were euthanized at 11 wk of age. Plasma NH2-terminal atrial natriuretic peptide (N-ANP) and aldosterone were determined (see below), and creatinine levels were measured using ELISA. Kidneys were weighed, and midcoronal slices were fixed in formalin and embedded in paraffin for immunohistochemical analysis.
For technical reasons (low blood pressure and oligoanuria at the time the animals were killed), no urine could be obtained from these animals for protein-to-creatinine ratio or urinary Kim-1 detection. Therefore, we studied urine samples (kindly provided by Prof. R. Kreutz, Department of Clinical Pharmacology, Charité University Medicine, Berlin, Germany) from separate 8-wk-old homozygous Ren2 animals that had been treated with the ACE inhibitor ramipril (Aventis Pharma Deutschland, Frankfurt am Main, Germany; 1 mg·kg–1·day–1 in drinking water) for 4 wk or were left untreated and from age-matched SD controls (all n = 7). To correlate urinary Kim-1 with renal Kim-1 expression, we performed Kim-1 immunohistochemistry and morphometric analysis on paraffin sections (see below).
We also studied Kim-1 expression in renal tissue from homozygous Ren2 rats that were euthanized at 7 wk (n = 5), 8 wk (n = 7), or 11 wk (n = 4) of age and from age-matched SD controls (n = 7 per time point).
Pharmacological interventions.
The AT1RA candesartan (a gift from AstraZeneca, Zoetermeer, The Netherlands) was dissolved in 0.1 M NaHCO3 in saline (0.9% NaCl) according to the manufacturer’s recommendations. The final dose administered was 0.05 mg·kg–1·day–1, which is a nonhypotensive dose in this model, as documented previously (1). Furthermore, the p38 MAP kinase inhibitor SB-239063 [trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-(2-methoxypyridi-midin-4-yl)imidazole; IC50 = 44 nM vs. p38; kindly provided by Dr. R. N. Willette, Dept. of Cardiovascular Pharmacology, GlaxoSmithKline, King of Prussia, PA] was dissolved in 0.1% DMSO in H2O, with 50% polyethylene glycol 400 (20). The final dose administered was 15 mg·kg–1·day–1. All drugs were administered by osmotic minipumps (types 2004 and 2ML4, depending on dose regimen, Alzet, Palo Alto, CA), which were aseptically filled by injection of the fluid containing the drug and weighed before and after they were filled. The volume weight injected was calculated to control for adequate filling of the pumps. Rats were anesthetized with 2–4% isoflurane in a gas mixture of 2:1 N2O-O2. Candesartan- and SB-239063-filled minipumps were inserted subcutaneously. When the animals were euthanized, the minipumps were collected and weighed for determination of the volume that was dispensed.
Aldosterone and N-ANP levels. Blood was obtained from the abdominal aorta, anticoagulated with EDTA, and immediately centrifuged (4°C, 1,500 g for 15 min). Plasma was stored at –80°C. For measurement of plasma aldosterone concentration (normal range 50–250 pg/ml), a commercially available kit (Coat-a-Count, Diagnostic Products, Los Angeles, CA) was used. Plasma N-ANP was measured with a commercially available radioimmunoassay kit (Biotop, Oulu, Finland). Both assays have been described previously (23).
Quantitative PCR for Kim-1 and osteopontin mRNA expression. Quantitative PCR (qPCR) analysis based on the TaqMan methodology was performed using an ABI Prism 7900 sequence detection system (Applied Biosystems, Foster City, CA). Primers and probe for the housekeeping gene GAPDH were designed using Primer Express Software (Applied Biosystems). Sequences of the primers and probe for housekeeping gene GAPDH mRNA are as follows: 5'-GAA CAT CAT CCC TGC ATC CA-3' (forward), 5'-CCA GTG AGC TTC CCG TTC A-3' (reverse), and 5'-CTT GCC CAC AGC CTT GGC AGC-3' (probe) (6). The Taqman probes were labeled at the 5' end with a reporter fluorochrome (FAM, i.e., 6-carboxyfluorescein) and at the 3' end with a quencher fluorochrome (TAMRA, i.e., 6-carboxytetramethylrhodamine). Kim-1 and osteopontin gene-specific Taqman probe and primer sets were obtained from Applied Biosystems as Assays-on-Demand (AOD) gene expression products. The AOD identification numbers were Rn00597703 m1 for Kim-1 and Rn00563571 m1 for osteopontin (Spp1).
Total RNA was extracted using the TRIzol method (Invitrogen, Carlsbad, CA). A DNase treatment was performed using Turbo DNase-free (Ambion, Austin, TX). cDNA was synthesized from 200 ng of total cellular RNA by a first-strand cDNA synthesis system using Superscript II RT (Invitrogen) with random hexamers in a volume of 20 µl and further diluted to 2 ng/µl. For GAPDH, the qPCR mixture contained 5 µl of cDNA, 10 µl of 2x TaqMan Universal PCR Master Mix (Eurogentec, Seraing, Belgium), 900 nmol/l of each primer, and 200 nmol/l probe in a total reaction volume of 20 µl. The qPCR mixture for the AOD products (Kim-1 and osteopontin) contained 10 µl of 2x Taqman Universal PCR Master Mix (Eurogentec), 1 µl of 20* AOD Gene Expression Assay Mix, and 5 µl of cDNA in a total reaction volume of 20 µl. All assays were performed in triplicate. Reaction tubes without template cDNA served as negative controls. The PCR plate was incubated for 2 min at 50°C to optimize the uracil-N-glycosylase enzyme activity and at 95°C for 10 min to activate the Taq polymerase. The reaction was then subjected to 40 cycles of denaturation at 95°C for 15 s, annealing, and extension at 60°C for 1 min. The threshold cycle (CT) was defined as the fractional cycle number at which the fluorescence generated by cleavage of the probe passed a preset threshold. The samples with CT >37 were considered not to express the given mRNA. The CT is inversely proportional to the logarithmic scale of the starting quantity of template cDNA. Consequently, the gene dosage was deduced by calculation of the difference in CT from the CT of the reference gene GAPDH. The average CT values for target genes were subtracted from the average housekeeping gene CT values to yield 
CT. Results were finally expressed as 2–CT, which is an index of the relative amount of renal Kim-1 mRNA expression.
Immunohistochemistry.
Paraffin sections (4 µm) were dewaxed and washed in PBS. Heat-induced antigen retrieval was achieved by incubation in 0.1 M Tris·HCl buffer (pH 9.0) overnight at 80°C. Sections were washed in PBS, and endogenous peroxidase was blocked by incubation with 0.3% H2O2 in PBS for 30 min. Then sections were incubated with primary antibodies against Kim-1 (Kim-1 peptide 9 polyclonal antibody, kindly provided by Dr. V. Bailly, BIOGEN, Cambridge, MA), -SMA (clone 1A4, Sigma, St. Louis, MO), osteopontin (anti-MPIIIB10, Developmental Studies Hybridoma Bank, Baltimore, MD), vimentin (clone V9, DakoCytomation, Glostrup, Denmark), or collagen III (Biogenesis, Milwaukee, WI). All primary antibodies were diluted in PBS containing 1% BSA for 60 min at room temperature. The Kim-1 peptide 9 polyclonal antibody has been described previously (7, 22). Binding was detected by sequential incubation with peroxidase-labeled rabbit anti-mouse, goat anti-rabbit, or rabbit anti-goat polyclonal antibodies (Dakopatts, Dako, Glostrup, Denmark) in the presence of 1% normal rat serum for 30 min. The peroxidase activity was visualized using 3,3'-diaminobenzidine tetrahydrochloride (DAB; Dako) for 10 min, and the section was mounted with Kaiser’s glycerin gelatin. A number of sections were counterstained with periodic acid-Schiff for photography.
Quantification of immunostaining.
The extent of interstitial -SMA, osteopontin, Kim-1, and collagen III expression was determined by computer-assisted morphometry, as described previously (2). Briefly, 30 interstitial fields were selected, glomeruli and arteries were excluded, and the amount of total brown precipitate was measured and represented as a percentage of the total selected area. The ultimate score was calculated by the average of all fields per section. All measurements were performed by a blinded observer.
Analysis of tubulointerstitial fibrosis. The extent of tubulointerstitial fibrosis (TIF) was determined in periodic acid-Schiff-stained sections among all groups. Thirty rectangular cortical fields were examined by a blinded observer at a magnification of x200. TIF was scored positive when tubular atrophy and broadening of the peritubular compartment were present simultaneously. Scores of 0–5 were assigned as follows: 0 indicated no interstitial fibrosis, 1 indicated 0–10% involvement of the rectangular field within the biopsy, 2 indicated 10–25% involvement, 3 indicated 25–50% involvement, 4 indicated 50–75% involvement, and 5 indicated 75–100% involvement.
Double-staining immunohistochemistry. Paraffin sections were prepared as described above (see Immunohistochemistry) and incubated in 0.3% H2O2 for 30 min. Sections were washed in PBS and incubated for 60 min with primary polyclonal antibodies against Kim-1 and primary monoclonal antibodies against SMA, osteopontin, or vimentin. Binding was detected by 30 min of incubation with peroxidase-labeled goat anti-rabbit polyclonal antibody (in the presence of 1% normal rat serum) and alkaline phosphatase-labeled goat anti-mouse antibodies. The sections were exposed to DAB for 10 min for visualization of the peroxidase activity, which illustrates Kim-1 immunoreactivity. Alkaline phosphatase activity was detected using naphthol AS-MX (Sigma), and color was developed with Fast Blue BB (Sigma) combined with levamisol and MgSO4 for 30 min for visualization of immunoreactivity for SMA, osteopontin, or vimentin, respectively. Sections were mounted with Kaiser’s glycerin gelatin.
For phosphorylated p38-Kim-1 double staining, a slightly different protocol was used. First, sections were stained with an anti-phosphorylated (Thr180/Tyr182) p38 monoclonal antibody (Cell Signaling Technology, Danvers, MA) according to the manufacturer’s protocol. Peroxidase-labeled goat anti-rabbit secondary antibodies and DAB were used for visualization of immunostaining. Then the sections were eluted by incubation in 0.1 M glycin (pH 2.5) for 60 min and incubated with Kim-1 polyclonal antibody and with alkaline phosphatase-labeled goat anti-rabbit antibody, respectively. Alkaline phosphatase activity was detected as described above.
Urinary Kim-1 measurement. Kim-1 protein in urine was measured by microsphere-based Luminex xMAPTM technology using monoclonal antibodies raised against rat Kim-1 in the Bonventre laboratory. This technique is an adaptation of the recently developed and validated sandwich ELISA assay, as described previously (21, 22). For measurements, 30 µl of 24-h urine were analyzed in duplicate.
Statistical analysis.
Values are means ± SE. Differences between the untreated Ren2 and SD groups were analyzed using Mann-Whitney’s U-test. The Kruskal-Wallis nonparametric test was used to compare results of the various treatments with the untreated Ren2 group. Correlations among Kim-1, osteopontin, and -SMA expression were calculated using Spearman’s 
nonparametric correlations. SD control animals were excluded from correlation analyses, because all values in SD groups were very low (around or under the detection limit). P < 0.05 was considered statistically significant. All data were analyzed using the SPSS 12.0.2 (SPSS, Chicago, IL) statistical software package.
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RESULTS |
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-SMA.
Data from morphometric analysis following immunohistochemical staining for Kim-1, osteopontin, and -SMA are presented in Fig. 2. In untreated Ren2 rats, Kim-1 protein was present in tubules within areas of TIF, where it was localized to the luminal side of cortical tubular epithelial cells (Fig. 3). Kim-1 protein expression was abolished in Ren2 rats treated with AT1RA or p38 MAP kinase inhibitor to values that were comparable to SD control animals (Figs. 2 and 3). In young (7-wk-old) homozygous Ren2 rats, Kim-1 was already significantly increased compared with SD controls, yet in older (8- or 11-wk-old) Ren2 rats, Kim-1 expression was more pronounced (Fig. 4). However, differential Kim-1 expression among Ren2 rats at the various time points did not reach statistical significance.
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-SMA in Ren2 rats, as expected (Fig. 2). Osteopontin was expressed in tubular epithelial cells and -SMA in smooth muscle cells and myofibroblasts (not shown). The decrease in osteopontin and -SMA protein expression to control values in AT1RA- and p38 inhibitor-treated Ren2 rats paralleled the decrease in Kim-1 expression. Urinary Kim-1 shedding. In untreated 8-wk-old homozygous Ren2 rats, urinary Kim-1 concentration was increased >15-fold compared with untreated SD rats (P < 0.01; Fig. 5). Treatment with the ACE inhibitor ramipril strongly reduced urinary Kim-1 toward SD control levels. Similar results were found in these animals for renal Kim-1 protein expression (Fig. 5). Urinary and renal Kim-1 expression correlated very strongly (r2 = 0.920, P < 0.0001).
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-SMA). First, we examined quantitative correlations between Kim-1, osteopontin, and -SMA. The amount of Kim-1 mRNA strongly correlated with osteopontin mRNA in all Ren2 animals (r2 = 0.847, P < 0.0001; Fig. 6A). At the protein level, Kim-1 and osteopontin were also correlated (r2 = 0.299, P < 0.01). We also found a strong correlation between protein expression of Kim-1 and -SMA (r2 = 0.607, P < 0.001; Fig. 6B).
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-SMA-positive interstitial myofibroblasts. Furthermore, in untreated Ren2 rats, the process of epithelial-to-mesenchymal transformation was induced, as evidenced by tubular vimentin expression. Tubular vimentin was absent in SD controls and Ren2 rats treated with the AT1RA or p38 inhibitor (data not shown). Kim-1 and vimentin colocalized only in a limited number of tubular epithelial cells (Fig. 6C).
Association of Kim-1 with TIF. We also studied the relation between renal Kim-1 expression and more advanced tubulointerstitial lesions. In untreated Ren2 rats, TIF and collagen III expression were induced compared with SD controls. Treatment with the AT1RA or the p38 inhibitor reduced TIF and collagen III expression (Fig. 7). We found significant correlations between renal Kim-1 expression and TIF (r2 = 0.427, P < 0.001) and collagen III expression (r2 = 0.536, P < 0.001).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Previous studies demonstrated the induction of Kim-1 in various models of renal damage; therefore, a role for this protein in the modulation of renal damage has been proposed. Inasmuch as specific pharmacological Kim-1 inhibitors or Kim-1-knockout mice are not available, there is no direct evidence for a functional role for Kim-1 in renal damage or repair. However, our data provide additional support for a role for Kim-1 in the development of renal damage or in response to injury.
In homozygous Ren2 rats, similar to ischemia-reperfusion injury (7, 14) and overload proteinuria (22), Kim-1 was mainly expressed in dilated and flattened cortical tubular epithelial cells. At 7 wk of age, Kim-1 was increased in Ren2 rats vs. SD controls; however, expression of Kim-1 was highest in 8-wk-old Ren2 rats (but not significantly increased compared with 7-wk-old Ren2 rats). In older (11-wk-old) Ren2 rats, Kim-1 expression remained similar; apparently, tubulointerstitial damage is stable from 8 wk of age in this model. This may well be related to the lower blood pressure due to heart failure in the homozygous Ren2 rat at this age. Tubular cell Kim-1 expression strongly correlated to and colocalized with established markers of tubulointerstitial prefibrotic damage, namely, osteopontin and -SMA. Moreover, we found that renal Kim-1 expression correlated with TIF and collagen III expression. Only a limited number of tubular epithelial cells were positive for both Kim-1 and vimentin. This suggests that Kim-1 and vimentin are expressed in separate stages of tubular epithelial cell dedifferentiation. These data are consistent with previous findings indicating that Kim-1 is relevant in tubular fibrotic damage (4, 22).
Moreover, we have shown that Kim-1 can be modulated by antifibrotic interventions, namely, RAS blockade or p38 MAP kinase inhibition. The beneficial effects of AT1 receptor blockade and MAP kinase inhibition on tubulointerstitial injury observed here are consistent with those reported previously, e.g., in human diabetic nephropathy (18) and endotoxin-induced tubular injury (25). In animals, the activated form of p38 is expressed in areas of tubulointerstitial damage, e.g., in puromycin amino nucleoside-induced renal disease (15). Similarly, using immunohistochemistry, we have shown that phosphorylated p38 is present in damaged tubular cells in the Ren2 model. Treatment with a specific p38 inhibitor reduced interstitial fibrosis in various models of renal disease, e.g., nitro-L-arginine methyl ester-treated spontaneously hypertensive rats (13) or unilateral ureteral obstruction (19). We have shown that AT1 receptor antagonism and p38 inhibition strongly reduce expression of Kim-1, which underscores its relevance as a marker of renal damage and suggests a functional role in tubular pathophysiology.
Treatment with an AT1RA or p38 inhibitor reduced Kim-1 protein expression to control levels. This marked reduction of Kim-1 may be directly related to inhibition of the RAS; alternatively, reduction of Kim-1 expression may result from indirect effects, such as improved hemodynamics. However, the latter is less likely, since our rats were normotensive in the time frame studied here (7–11 wk of age) and we used a nonhypotensive dose of the AT1RA. Since tubules within areas of TIF expressed activated p38 and Kim-1, it may be that the p38 inhibitor exerted direct effects on Kim-1 expression and/or tubular damage. Irrespective of the mechanism of reduction, our findings that Kim-1 is induced in Ren2 rats and that AT1 receptor blockade and MAP kinase inhibition, known antifibrotic interventions, evidently reduce Kim-1 expression support involvement of Kim-1 expression in RAS-induced tubular damage.
The extracellular part of Kim-1 can be shed into the tubular lumen; this ectodomain shedding is mediated by matrix metalloproteinases, possibly involving MAP kinase activation (24). In vivo the Kim-1 ectodomain may protect proximal tubular cells against protein casts that are formed within the tubular lumen or prevent the tubular cast formation. Nevertheless, since the homozygous Ren2 model is not characterized by gross proteinuria (2), Kim-1 shedding may also be involved in a more general tubuloprotective mechanism. Although the pathophysiological implications of Kim-1 shedding are unclear, it can be used as a urinary biomarker (4, 5). We demonstrated that, in untreated Ren2 rats, Kim-1 shedding, which could be modulated by ACE inhibition, is induced. Furthermore, we confirmed the previously reported correlation between urinary and renal tissue Kim-1 (22).
We observed epithelial cells that are positive for phosphorylated p38 and Kim-1 in areas of tubular damage, which is consistent with previous findings that Kim-1 shedding may be mediated by p38 MAP kinase activation. Some of the Kim-1-positive cells did not express activated p38, which may indicate that not all tubular cells are actively shedding Kim-1 simultaneously. Unfortunately, for technical reasons, no urine was available from Ren2 rats treated with a p38 MAP kinase inhibitor. Nevertheless, this is the first demonstration that shedding of Kim-1 into the urine can be modulated, in this case, by ACE inhibition.
In conclusion, we found that tubular Kim-1 expression, which is induced in RAS-mediated tubulointerstitial injury, can be modulated by AT1 receptor blockade or p38 inhibition. Damaged tubular epithelial cells were Kim-1 positive, and tubular Kim-1 expression correlated with tissue osteopontin and -SMA expression and colocalized with these two markers of tubulointerstitial damage. Furthermore, renal Kim-1 expression correlated with TIF and interstitial collagen III deposition. Although further studies are required to clarify the role of Kim-1 in renal pathophysiology, these data suggest that Kim-1 may contribute to the development of tubular injury mediated by the RAS.
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ACKNOWLEDGMENTS |
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Part of this work was presented at the 38th Annual Meeting of the American Society of Nephrology, Philadelphia, PA, November 2005.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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mitogen-activated protein kinase activation in renal fibrosis. J Am Soc Nephrol 15: 370–379, 2004.This article has been cited by other articles:
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