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Am J Physiol Renal Physiol 293: F1123-F1130, 2007. First published July 18, 2007; doi:10.1152/ajprenal.00104.2007
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Renal inflammation is modulated by potassium in chronic kidney disease: possible role of Smad7

Wansheng Wang, Liliana Soltero, Ping Zhang, Xiao R. Huang, Hui Y. Lan, and Horacio J. Adrogue

Department of Medicine-Renal Section, Baylor College of Medicine, Houston, Texas

Submitted 28 February 2007 ; accepted in final form 17 July 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
High-potassium diets have been shown to be beneficial in cardiovascular disease partly because of a blood pressure-lowering effect. The effect of potassium on inflammation has not been studied. We investigated the influence of potassium supplementation on the degree of renal inflammation and the intracellular signaling mechanisms that could mediate inflammation in chronic kidney disease (CKD). CKD was created in male Sprague-Dawley rats by subtotal nephrectomy. Two groups of CKD rats were pair fed with diets containing 2.1% potassium (potassium-supplemented diet) or 0.4% potassium (basal diet). Body weight, blood pressure, and blood and urine electrolytes were measured biweekly. The animals were euthanized at week 8, and the remnant kidneys were analyzed by histology, immunohistochemistry, Western blotting, and real-time quantitative PCR. In the CKD pair-fed groups, blood potassium concentration did not differ significantly, but blood pressure was lower in the potassium-supplemented group. Compared with the basal diet, potassium supplementation decreased renal tubulointerstitial injury and suppressed renal inflammation as evidenced by decreased macrophage infiltration, lower expression of inflammatory cytokines, and decreased NF-{kappa}B activation. These renoprotective effects were associated with downregulation of renal transforming growth facto-beta, upregulation of renal Smad7, and lower blood pressure. Our results show that potassium supplementation can reduce renal inflammation and hence, could modulate the progression of kidney injury in CKD.

NF-{kappa}B; potassium; Smad7; TGF-beta

THE MEDIATORS OF PROGRESSIVE chronic kidney disease (CKD) remain largely unsolved, especially the mechanisms leading to progressive fibrosis of the kidney. The presence of fibrosis in the kidney is generally preceded by glomerular and tubulointerstitial infiltration by inflammatory cells. It is likely that the infiltrating inflammatory cells activate NF-{kappa}B, leading to the production and release of proinflammatory cytokines and adhesion molecules (e.g., IL-1beta, ICAM-1) as well as profibrotic cytokines [e.g., transforming growth factor (TGF)-beta]. The consequence is renal inflammation and progressive fibrosis of the kidney, leading to loss of function. Treatment strategies have included medications and dietary modifications such as limitation of protein and sodium intake to reduce the accumulation of potential uremic toxins and blood pressure. The potential influence of potassium intake on progressive kidney disease remains largely unknown.

There are indications that potassium supplementation may be beneficial in cardiovascular diseases, especially for problems arising as a complication of hypertension (7, 17, 20, 27, 38). There are also indications that potassium supplementation might reduce local vascular inflammatory reactions. Ishimitsu et al. (16) reported that potassium supplementation suppressed macrophage activity in stroke-prone spontaneously hypertensive rats (SHPsp). In their study, the rats were fed a normal or high-potassium diet, and excised aortas were perfused with macrophages. Potassium supplementation tended to protect against inflammation because the number of macrophages infiltrating the aorta was 158% higher in the rats fed a normal diet compared with results in the potassium supplementation group (16).

There also is evidence that potassium could influence the course of kidney diseases. Tobian et al. (39) reported that adding either 4% potassium citrate or 2.6% potassium chloride to the diet of salt-sensitive Dahl S rats slowed the progression of renal injury even though there was no significant change in their blood pressures. Pere et al. (29, 30) reported that a high-potassium diet (2.4% potassium) is renoprotective in cyclosporine-induced nephrotoxicity, compared with a diet containing 0.8% potassium. In contrast, chronic potassium depletion causes renal functional deterioration, interstitial nephritis, or cyst formation in animals and humans (3, 4, 6, 11, 32, 34, 40, 47). The proposed underlying mechanisms of the deleterious effect of potassium depletion include activation of the local renin-angiotensin II system (RAS) (32), increased angiotensin II receptor (AT1) expression (12), and altered activity of the sodium-potassium pump in the renal tubule (35), acting by blood pressure-dependent and/or blood pressure-independent mechanisms.

We examined the influence of potassium supplementation on the degree of renal inflammation in the subtotal nephrectomy model of CKD in rats. Our results indicate that potassium supplementation can reduce inflammatory processes in the kidney, and the degree of renal injury.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Remnant kidney disease model. A model of CKD was developed in Sprague-Dawley rats (250–300 g body wt, 3-mo-old males) by subtotal nephrectomy as described (46). Briefly, the rats were anesthetized, the right kidney was removed, and 2/3 nephrectomy of the left kidney was achieved by renal artery ligation. Sham control rats (n = 6) had a laparotomy but no damage to the kidney. Two groups of rats with a subtotal nephrectomy (n = 5) were pair fed with a diet containing 2.1% potassium (potassium supplementary diet) or 0.4% potassium (basal diet) after surgery, as described previously (1). Sham controls were fed the basal diet ad libitum. Twenty-four-hour urine was collected using metabolic cages for all CKD rats and three sham controls, and blood was drawn from the tail vein biweekly. The body weight and systolic blood pressure (SBP) were measured biweekly. SBP was measured in restrained, conscious rats by the standardized tail-cuff method (31). The animals were euthanized at week 8, and kidneys were collected for histology, immunohistochemistry, Western blotting, and real-time PCR analyses. The experimental procedures were approved by Animal Experimental Committee at Baylor College of Medicine.

Urine excretion of angiotensin II and aldosterone. The 24-h urine excretion of angiotensin II and aldosterone at weeks 0, 2, and 8 were measured by commercial ELISA kits (Cayman Chemical, Ann Arbor, MI) according to the manufacturer's instructions.

Histology and immunohistochemistry. Renal morphology was examined in methyl Carnoy's-fixed, paraffin-embedded tissue sections (4 µm) after they were stained with hematoxylin and eosin or periodic acid-Schiff (PAS). The percentage of glomerular sclerosis was measured by using a quantitative image-analysis system (Optima 6.5; Media Cybernetics, Silver Spring, MD). Briefly, an area of the glomerulus was outlined; positive staining patterns were identified, and the percent positive area in the examined glomerulus was then measured. A minimum of 20 glomeruli/animal was calculated. The spaces in Bowman's capsule were excluded. Renal interstitial fibrosis was assessed by morphometric measurement of interstitial volume as described (41). Briefly, the interstitial volume was measured as the percentage of grid points using a 1-cm2-graded ocular grid, which is situated within the interstitial area, views at x20 magnification. Five to 10 random fields were used for morphometry. The infiltration of macrophages and the activation of NF-{kappa}B were determined by three-layer immunohistochemistry with monoclonal antibodies to macrophages (CD68, Serotec) and rabbit polyclonal antibodies to NF-{kappa}B-p65 (Santa Cruz Biotechnology, Santa Cruz, CA). Immunostaining for macrophages was performed in 2% paraformaldehyde-lysine-periodate-fixed frozen sections as previously described (19), while detection of NF-{kappa}B/p65 subunits was performed in methyl Carnoy's-fixed paraffin sections using a microwaved-based antigen retrieval technique. After being developed with 3,3-diaminobenzidine, sections were counterstained with hematoxylin. Nuclear-positive staining for NF-{kappa}B/p65 was counted as NF- {kappa}B-activated cells (44). Glomerular and tubulointerstitial NF-{kappa}B-activated cells and infiltrating macrophages were counted and expressed as positive cells per glomerulus or per square centimeter tubulointerstitial area as previously described (19).

Western blot analysis. Protein from kidney tissues was extracted with RIPA lysis buffer (1% Nonidet P-40, 0.1% SDS, 1 mM phenylmethylsulfonyl fluoride, 0.5% sodium deoxycholate, 1 mM sodium orthovanadate, 1 mM sodium fluoride in PBS). After determination of protein concentrations, 20 µg of protein was mixed with an equal amount of 2x SDS loading buffer (100 mM Tris·HCl, 4% SDS, 20% glycerol, and 0.2% bromophenol blue) for Western blot analysis. Briefly, samples were heated at 99°C for 5 min and then transferred to a polyvinylidene difluoride (PVDF) membrane. Nonspecific binding to the membrane was blocked for 1 h at room temperature with 5% BSA in Tris-buffered saline buffer (TBST; 20 mM Tris·HCl, 150 mM NaCl, and 0.1% Tween 20). The membranes were then incubated overnight at 4°C with primary antibodies against collagen type I, type III (Southern Biotech, Birmingham, AL), TGF-beta, Smad7 (Santa Cruz), anti-phospho-I{kappa}B-{alpha} (pI{kappa}B{alpha}), anti-I{kappa}B{alpha} (Cell Signal, Danvers, MA), anti-GAPDH (Chemicon, Temecula, CA). After being washed extensively, the membranes were then incubated with horseradish peroxidase-conjugated secondary antibody for 1 h at room temperature in 1% BSA/TBST. The signals were visualized by an enhanced chemiluminescence system (Amersham, Piscataway, NJ).

Real-time PCR. Total kidney RNA was isolated using the RNeasy kit, according to the manufacturer's instructions (Qiagen, Valencia, CA). The cDNA was synthesized as previously described (45), and real-time PCR was run with the Opticon real-time PCR machine (MJ Research, Waltham, MA). The specificity of real-time PCR was confirmed via routine agarose gel electrophoresis and melting-curve analysis. The housekeeping gene GAPDH was used as an internal standard. The primers used in this study are as follows: collagen I: forward 5'-TGCCGTGACCTCAAGATGTG, reverse 5'-CACAAGCGTGCTGTAGGTGA; collagen III: forward 5'-GCGGAATTCCTGGACCAAAAGGTGATGCTG, reverse 5'-GCGGGATCCGAGGACCACGTTCCCCATTATG; CAM-1: forward 5'-TCAGGTATCCATCCATCCCAGAGA, reverse 5'-AGCTCATCTTTCAGCCACTGAGTC; IL-1beta: forward 5'-CTTCAGGCAGGCAGTATCACTCAT, reverse 5'-TCTAATGGGAACGTCACACACCAG; and GAPDH forward 5'-CCTGGAGAAACCTGCCAAGTATGA, reverse 5'-TTGAAGTCACAGGAGACAACCTGG.

Statistical analyses. Data are expressed as means ± SE. Statistical analyses were performed using one-way analysis of variance or t-test from GraphPad Prism 3.0 (GraphPad Software, San Diego, CA).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Blood pressure, electrolytes, body weight, and serum creatinine. A progressive increase in SBP occurred in both CKD groups, but rats fed the potassium supplementary diet had lower SBP at all the points of observation; the difference was statistically significant at weeks 6 and 8 (Fig. 1A). Despite receiving potassium supplementation, the serum potassium concentration was only slightly increased at weeks 2 and 4 (Fig. 1D). There was no significant difference between two groups of CKD rats in serum creatinine concentration (Fig. 1B). As expected from pair-feeding technique, there was no significant difference in body weight gain (Fig. 1C).


Figure 1
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  		Fig. 1. Effect of potassium supplementation on blood pressure, serum creatinine concentration, serum potassium concentration, and body weight gain. A: systolic blood pressure. B: serum creatinine concentration. C: body weight gain biweekly. D: serum potassium concentration. Values are means ± SE. Gray bars, sham control, n = 3; black bars, basal diet group, n = 5; open bars, potassium supplementation, n = 5. #Statistically significant difference, sham compared with basal diet or high-potassium diet group. *P < 0.05 high-potassium diet group compared with basal diet group.

 
Urine sodium, potassium, aldosterone, and angiotensin II excretion. Potassium supplementation led to an about twofold increase in urine potassium excretion (Fig. 2A). There was no statistical difference in urine sodium or protein excretion (Fig. 2B). Moreover, there was no significant difference in the urine excretion of aldosterone and angiotensin II between the two CKD groups (Fig. 2, D and E).


Figure 2
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  		Fig. 2. Effect of potassium supplementation on daily urinary excretion of potassium sodium, protein, aldosterone, and angiotensin II. A: daily urinary potassium excretion. B: daily urinary sodium excretion. C: daily urinary protein excretion. D: daily urinary excretion of aldosterone. E: daily urinary excretion of angiotensin II. Values are means ± SE. Gray bars, sham control, n = 3; open bars, basal diet group, n = 5; black bars, potassium supplementation, n = 5. #Statistically significant difference, sham compared with basal diet or high-potassium diet group. *P < 0.001 high-potassium diet group compared with basal diet group.

 
Renal histology. Glomerulosclerosis and interstitial fibrosis were evident in the remnant kidney (Fig. 3A). Compared with the basal diet, potassium supplementation resulted in significantly less interstitial fibrosis, but no significant difference was found in the degree of glomerulosclerosis (Fig. 3, B–D). Since renal fibrosis is characterized by excessive expression and deposition of extracellular matrix (ECM), including collagen type I and III, we used real-time quantitative PCR and Western blot assay to assess the expression of collagen type I and III in the remnant kidney. Both methods consistently showed significantly less renal collagen type I and III deposition in the remnant kidneys of rats supplemented with potassium (Fig. 4).


Figure 3
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  		Fig. 3. Effect of potassium supplementation on histological damage in remnant kidneys after subtotal nephrectomy. A: representative image of renal histology in basal diet group [periodic acid-Schiff (PAS) staining, x200]. B: representative image of renal histology in potassium-supplemented group (PAS staining, x200). C: quantitative analysis of renal tubulointerstitial injury as described in METHODS. D: quantitative analysis of renal glomerulosclerosis as described in METHODS. Values are means ± SE. Gray bars, sham control, n = 6; open bars, basal diet group, n = 5; black bars, potassium supplementation, n = 5. #Statistically significant difference, sham compared with basal diet or high-potassium diet group. *P < 0.05 high-potassium diet group compared with basal diet group.

 

Figure 4
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  		Fig. 4. Western blot and real-time quantitative PCR reveal that potassium supplementation inhibits renal fibrosis in the remnant kidneys. A: total protein extracted from the renal tissues was subject to Western blot analysis of collagen types I and III. Glyceraldehydes-3-phosphate dehydrogenase (GAPDH) serves as a loading control. B: densitometric analysis of expression of renal collagen types I and III. C: total RNA extracted from renal tissues was subject to reverse transcription and quantitative real-time PCR analysis for collagen types I and III, normalized by GAPDH. Values are means ± SE. Gray bars, sham control, n = 6; open bars, basal diet group, n = 5; black bars, potassium supplementation, n = 5. #Statistically significant difference, sham compared with basal diet or high-potassium diet group. *P < 0.05 high-potassium diet group compared with basal diet group.

 
Renal inflammation. There was increased infiltration of macrophages in both glomerular and tubulointerstitial areas of the remnant kidney in both CKD groups (Fig. 5A). The infiltration of macrophages was accompanied by significant upregulated expression of inflammatory cytokines, as analyzed by quantitative real-time PCR (Fig. 6, A and B). Notably, potassium supplementation significantly suppressed infiltration of macrophages and the expression of inflammatory cytokines (Figs. 5, B–D, and 6, A and B). Since NF-{kappa}B can plan a pivotal role in the development of renal inflammation, we measured renal I{kappa}B{alpha} and phospho-I{kappa}B{alpha} (pI{kappa}B{alpha}) level as well as nuclear NF-{kappa}B-p65 translocation in the remnant kidney (44). As demonstrated by Western blotting, the level of pI{kappa}B{alpha} was lower while I{kappa}B{alpha} level was significantly higher in the remnant kidney of rats given potassium supplementation (Fig. 7, A and B ). Supporting this observation, the NF-{kappa}B-p65 nuclear translocation was decreased in these rats. These results suggest that there was decreased activation of NF-{kappa}B in the remnant kidney of rats supplemented with potassium (Fig. 7, C–F).


Figure 5
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  		Fig. 5. Effect of potassium supplementation on macrophage infiltration in rat remnant kidneys. A: representative image of renal macrophage infiltration in basal diet rats. B: representative image of renal macrophage infiltration in potassium-supplemented rats. C: quantitative analysis of glomerular macrophage infiltration. D: quantitative analysis of tubulointerstitial macrophage infiltration Values are means ± SE. Gray bars, sham control, n = 6; open bars, basal diet group, n = 5; black bars, potassium supplementation, n = 5. #Statistically significant difference, sham compared with basal diet or high-potassium diet group. **P < 0.01, high-potassium diet group compared with basal diet group.

 

Figure 6
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  		Fig. 6. Real-time quantitative PCR reveals that potassium supplementation inhibits renal inflammatory cytokine and adhesion molecule expression. Total RNA extracted from renal tissues was subject to reverse transcription and quantitative real-time PCR analysis of IL-1beta and ICAM-1 expression, normalized by GAPDH. Values are means ± SE. Gray bars, sham control, n = 6; open bars, basal diet group, n = 5; black bars, potassium supplementation, n = 5. #Statistically significant difference, sham compared with basal diet or high-potassium diet group; *P < 0.05 high potassium-diet group compared with basal diet group.

 

Figure 7
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  		Fig. 7. Potassium supplementation inhibits NF-{kappa}B activation in this rat remnant kidney disease model. A: total protein extracted from renal tissues was subject to Western blot analysis of p-I{kappa}B{alpha} and I{kappa}B{alpha} levels. GAPDH served as loading control. B: densitometric analysis of renal pI{kappa}B{alpha} and I{kappa}B{alpha} levels. C: immunohistochemistry shows massive NF-{kappa}B activation in the kidney of basal diet rats. D: immunohistochemistry shows that potassium supplementation inhibits renal NF-{kappa}B activation. E and F: quantitative analysis of glomerular and tubulointerstitial NF-{kappa}B activation. Values are means ± SE. Gray bars, sham control, n = 6; open bars, basal diet group, n = 5; black bars, potassium supplementation, n = 5. #Statistically significant difference, sham compared with basal diet or high-potassium diet group. *P < 0.05, **P < 0.01: high-potassium diet group compared with basal diet group.

 
Renal expression of TGF-beta and Smad7. Because TGF-beta and Smad7 play a critical role in the pathogenesis of progressive kidney injury, we examined the levels of TGF-beta and Smad7 in the remnant kidney. We found that potassium supplementation significantly increased renal Smad7 expression compared with levels in the remnant kidneys from the basal diet. In contrast, potassium supplementation decreased renal TGF-beta expression (Fig. 8, A and B).


Figure 8
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  		Fig. 8. Potassium supplementation significantly increases renal Smad7 expression and decreased renal TGF-beta expression. A: total protein from renal tissues was subject to Western blot analysis for Smad7 and TGF-beta. GAPDH served as loading control. B: densitometric analysis of renal Smad7 and TGF-beta expression Values are means ± SE. Gray bars, sham control, n = 3; open bars, basal diet group, n = 5; black bars, potassium supplementation, n = 5. #Statistically significant different, sham compared with basal diet or high-potassium diet group. *P < 0.001 high-potassium diet group compared with basal diet group.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Our results in a standard rat model of CKD demonstrate that potassium can play an important role in modulating renal inflammation. Specifically, we found that potassium supplementation 1) decreased the degree of interstitial histological injury and 2) suppressed renal inflammation as evidenced by decreased macrophage infiltration, lower expression of inflammatory cytokines, and decreased NF-{kappa}B activation. We postulate that the renoprotective mechanisms could be decreased renal TGF-beta expression, upregulated renal Smad7 expression, and a reduction of blood pressure.

NF-{kappa}B plays a crucial role in mediating inflammation in the kidney because NF-{kappa}B regulates the expression of numerous genes involved in inflammation, including cytokines and adhesion molecules. In the resting state, cellular NF-{kappa}B dimers remain in the cytoplasm bound to the inhibitory subunit I{kappa}B{alpha}, which renders NF-{kappa}B inactive. Activation of NF-{kappa}B occurs when I{kappa}B{alpha} is phosphorylated in response to a number of stimuli, leading to I{kappa}B{alpha} ubiquitinylation and, ultimately, degradation by the proteasome. Therefore, NF-{kappa}B is released into the nucleus and regulates the transcription of target genes (2). Extensive in vitro studies in renal mesangial and tubular epithelial cells have demonstrated that NF-{kappa}B activation leads to upregulation of inflammatory gene expression (10, 14, 23, 26, 28, 33). Blockade of the NF-{kappa}B pathway can alleviate inflammatory reactions (5, 8, 22, 25, 37). In short, NF-{kappa}B plays a central role in mechanisms causing renal inflammation. In this study, we found that potassium supplementation decreased NF-{kappa}B activation even though there was no change in serum potassium concentration. Our results also show that the suppression of NF-{kappa}B activation is accompanied by upregulation of Smad7, an inhibitory Smad in the TGF-beta/Smad signaling pathway, in the remnant kidney. This is relevant because Smad7 can function as an inhibitor of the inflammatory NF-{kappa}B signaling pathway as well as an inhibitor of the fibrotic TGF-beta/Smad signaling pathway (21, 44). Our previous studies demonstrated that Smad7 plays an important role in the regulation of renal inflammation and fibrosis. For example, overexpression of Smad7 in the kidney inhibited renal fibrosis through a mechanism that not only involves inhibition of receptor-Smads activation but also an upregulation of I{kappa}B{alpha} to suppress NF-{kappa}B activation and inflammation (21, 44).

We also found that potassium supplementation decreased TGF-beta expression in the remnant kidneys. There are extensive in vitro studies demonstrating that TGF-beta can upregulate Smad7 expression (24). However, in animal studies the association between TGF-beta and Smad7 expression has been inconsistent. For example, Uchida et al. (42) and Fukasawa et al. (13) reported that renal I-Smads Smad6/Smad7 were decreased in rat anti-Thy1 model and mouse UUO models, despite dramatic upregulation of TGF-beta expression in the kidney. In agreement with aforementioned reports, we have found that a mouse unilateral uretheral obstructive model had a discrepancy between renal TGF-beta and Smad7 expression levels. We do not know why the in vivo results differ from in vitro findings, but our results indicate that the renoprotective effect of potassium supplementation is associated with upregulation of Smad7 and downregulation of TGF-beta in the remnant kidney.

High blood pressure is an important mediator in the progressive nature of CKD. In this study, the results show that potassium supplementation did not lead to substantial hyperkalemia, suggesting that part of supplementary potassium is replete in the intracellular potassium pool. Our results also show that potassium supplementation lowered blood pressure in this model of CKD, even though serum potassium level was almost unchanged, and this effect was independent of dietary protein, calories, sodium, or other nutrients because the rats were pair fed (Fig. 1). There are reports suggesting that high dietary potassium exerts a natriuretic and diuretic effect that could contribute to the lowering of blood pressure (27, 36). But we found no difference in urinary sodium excretion between CKD groups. We then assessed whether the production of aldosterone or angiotensin II contributed to the antihypertension effect of a high-potassium diet, and our further study showed that a high-potassium diet lowers blood pressure in this CKD model by a manner independent on aldosterone and angiotensin II production, because no significant difference was found in urine aldosterone/angiotensin II excretion (Fig. 2, D and E). We have not identified how dietary potassium supplementation lowers blood pressure. Possible explanations include a dilatation of blood vessels. For example, our previous study suggested that a high-potassium diet vasodilates vessels by stimulating the activity of Na+-K+-ATPase to decrease cytosolic Ca2+ concentration (9). A high-potassium diet might also enhance endothelium-dependent relaxation and increase nitric oxide synthesis to dilate blood vessels (48). Regardless of the mechanism, the blood pressure-lowering effect of dietary potassium was only moderate but could be very important, since there are beneficial effects on local tissue/organ structure and function in some interventional studies (15, 18, 43).

In summary, we have demonstrated that potassium supplementation in amounts that do not lead to severe hyperkalemia exert a renoprotective effect in a standard rat CKD model. Upregulation of Smad7 expression in the kidney and inhibition of NF-{kappa}B activation are suggested mechanisms for the renoprotective effect against renal inflammation. The antihypertensive effects of potassium as well as downregulation of renal TGF-beta expression could also contribute to renoprotection. These results suggested that careful modification of dietary potassium intake maybe important in the management of CKD.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by National Institutes of Health Grants RO1-HL-076661, RO1-DK-062828, and P50-DK-064233.


   ACKNOWLEDGMENTS
 
The authors thank Dr. William Mitch for help in the experiment design and writing of the manuscript.


   FOOTNOTES
 

Address for reprint requests and other correspondence: W. Wang, Dept. of Medicine-Renal Section, Baylor College of Medicine, One Baylor Plaza, Alkek N520, Houston, TX 77030 (e-mail: wanshengwang{at}yahoo.com)

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.


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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