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Pathophysiology of Renal Disease and Progression |
* Los Angeles Biomedical Research Institute, Torrance, California; Division of Nephrology, Vanderbilt University, Nashville, Tennessee; and National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
Address correspondence to: Dr. Raimund Hirschberg, LABiomed, C-1-A, 1124 West Carson Street, Torrance, CA 90502. Phone: 310-222-3891; Fax: 310-782-1837; E-mail: rhirschberg{at}labiomed.org
Received for publication March 26, 2006. Accepted for publication July 2, 2006.
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Abstract |
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and is associated with a loss of renal bone morphogenic protein-7 (BMP-7) expression. Here, the hypothesis that maintenance of renal (especially podocyte) BMP-7 by transgenic expression reduces diabetic renal injury was tested. Diabetic mice that expressed the phosphoenolpyruvate carboxykinase promoter–driven BMP-7 transgene and nondiabetic, transgenic mice as well as diabetic and nondiabetic wild-type controls were studied for up to 1 yr. Transgenic expression of BMP-7 in glomerular podocytes and proximal tubules prevents podocyte dropout and reductions in nephrin levels in diabetic mice. Maintenance of BMP-7 also reduces glomerular fibrosis and interstitial collagen accumulation as well as collagen I and fibronectin expression. Diabetic wild-type mice develop progressive albuminuria, which is substantially reduced in transgenic mice. These effects of the BMP-7 transgene occur without changing renal TGF- levels. It is concluded that maintenance of renal BMP-7 during the evolution of diabetic nephropathy reduces diabetic renal injury, especially podocyte dropout. The findings also establish a role for endogenous glomerular BMP-7 as an autocrine regulator of podocyte integrity in vivo. |
Introduction |
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family, growth differentiation factors, Müllerian inhibitory substance, activins/inhibin, lefty and nodal, the TGF- superfamily of cysteine-knot cytokine growth factors. BMP-7 plays pivotal roles in kidney and eye development (1). In adult organisms, BMP-7 is selectively expressed in only a few tissues, and the kidneys are among the organs with the highest expression. In the kidney, BMP-7 is expressed mainly in tubules of the outer medulla and in glomerular visceral epithelial cells (podocytes).
Members of the TGF- superfamily of proteins use a series of type I and II receptors for initiation of cellular signals. Binding of a ligand to the type II receptor with constitutive serine/threonine kinase activity causes recruitment of a type I receptor into a heterodimeric receptor complex. Activation by phosphorylation of the type I receptor serine/threonine kinase induces serine phosphorylation of cellular substrates, notably receptor Smad. In most tissues, TGF- causes Smad2/3 activation, whereas BMP activate Smad1, 5, and 8 (2,3). In renal epithelial cells, BMP-7 uses preferably or exclusively Smad5 (4).
Whereas TGF- is the single most prominent cytokine in renal fibrosis, pharmacologic BMP-7 has emerged recently as an antifibrogenic agent in the kidney. In experimental, unilateral obstructive nephropathy or diabetic glomerular sclerosis, exogenously administered rhBMP-7 reduces renal fibrosis (5,6). The mechanisms of BMP-7’s antifibrogenic actions have been explored in vitro and involve BMP-7–induced Smad signals that block activation and nuclear translocation of TGF-–induced Smad2/3 (4). Thus, in cultured cells, BMP-7 acts as a counterregulator of TGF-’s profibrogenic actions (7). In experimental diabetes in rodents, renal levels of BMP-7 decrease early, predating onset and progression of structural damage to the kidneys (8). The decrease of renal BMP-7 may favor TGF-–driven fibrogenesis. In these in vivo experimental studies, we examined whether endogenous renal BMP-7 prevents early podocyte injury and has antifibrogenic activity in glomeruli and the renal tubulointerstitium. We tested the hypothesis that overexpression of BMP-7 during diabetes by means of a phosphoenol-pyruvate carboxykinase (PEPCK) promoter–driven transgene retards onset and progression of diabetic nephropathy in mice with special emphasis on early glomerular injury. PEPCK–BMP-7 transgenic (TG) mice were made diabetic with streptozotocin and studied for up to 1 yr along with nondiabetic BMP-7 transgenic mice and diabetic and nondiabetic, wild-type (WT) controls.
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Materials and Methods |
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Seven phenotypically normal founder lines were identified and mated onto WT FVB/N mice to generate hemizygous F1 mice. Transgene expression was detected in three of these lines (D1, D3, and D5) by Western blot analysis using the BMP-7 mAb 12G3 (provided by Kuber Sampath, Curis Corp., Cambridge, MA) and/or by Northern blot analysis of whole kidney, fat, and liver RNA using the SV40 poly A tail probe. The strongest transgene expression was seen in line D1, and homozygous male descendants were used in these studies.
Forty TG and WT mice were made diabetic with repeated intraperitoneal injections of streptozotocin (Sigma, St. Louis, MO), 50 mg/kg in 50 mM citrate buffer (pH 4.8), on five consecutive days. Two days after the last injection, tail-tip blood glucose was measured with a glucometer (Encore; Bayer Corp., Elkhart, IN). Mice with blood glucose 
350 mg/dl were maintained with free access to laboratory food and drinking water. Similar numbers of TG and WT, nondiabetic mice were maintained in parallel as controls. Thus, four groups of mice were studied: WT, nondiabetic controls (WT-Co), WT diabetic mice (WT-D), BMP-7–TG, nondiabetic controls (TG-Co), and BMP-7–TG mice with diabetes (TG-D). Periodically, blood glucose was measured and timed urine was collected and cleared by centrifugation, and urine aliquots were frozen at –80°C for quantitative measurement of albuminuria. At 4, 16, and 52 wk, aliquots of mice from each of the four groups (n = 8 to 11) were anesthetized, blood was obtained by aortic puncture, and kidneys were removed. One-millimeter coronal kidney sections were obtained and processed.
One hundred glomerular tufts that were free of Bowman’s capsule and tubular elements were microdissected manually on ice under a dissection microscope from aliquot renal sections from six animals in each group at each of the three time points in recombinant RNasin ribonuclease inhibitor (Promega, Madison, WI) for subsequent RNA extraction. Total RNA also was extracted from whole kidney sections using RNA Stat-60 reagent and the manufacturer’s recommended procedure (Tel-Test, Friendswood, TX). Additional kidney aliquots were shock-frozen in liquid N2 and stored at –80°C.
Additional coronal kidney slices were fixed in buffered paraformaldehyde for histologic and immunohistologic studies. For protein analyses, the wet weights of aliquots of kidney were measured with an analytical microbalance; tissues were minced and homogenized in 10 µl/mg extraction buffer (50 mM HEPES, 50 mM tetrasodium pyrophosphate, 100 mM sodium fluoride, and 10 mM EDTA [pH 7.4], containing 10 mM Na-orthovanadate and protease inhibitor cocktail [Roche, Penzberg, Germany]), kept on ice for 15 min, cleared by centrifugation, and stored at –80°C.
Serum levels of total and glycated albumin were measured with the BCG-albumin assay (BioAssay Systems, Haywood, CA) and a specific ELISA assay (Glyco-Albumin M; Exocell Inc., Philadelphia, PA), respectively. Albumin was measured in triplicate in diluted urine with a mouse-specific, sensitive, double-antibody ELISA assay (Bethyl, Montgomery, TX). Urea nitrogen and creatinine concentrations in sera were measured with the urease-glutamate dehydrogenase and the kinetic Jaffe methods, respectively, on the Cobos Mira automated assay system (Roche Diagnostic Systems, Montclair, NJ). The studies that involved animals were performed with adherence to the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by institutional review boards.
Cell Cultures
Cultured murine mesangial cells and mouse podocytes were used to assess the expression of the PEPCK enzyme in comparison with isolated glomeruli and mouse whole kidney. Murine mesangial cells (ATCC, Manassas, VA) were cultured in DMEM/F12 that contained 10% FCS. Murine podocytes were donated by K. Endlich (University of Heidelberg, Heidelberg, Germany) and have been characterized in detail previously (10). Podocytes were grown at 33°C in collagen I–coated culture flasks in RPMI 1640 that contained 10% FCS and IFN-
(10 U/ml) and then thermo-shifted and incubated at 37°C in IFN-free medium for 2 wk for differentiation.
Biochemical Assays
BMP-7 levels in sera and renal extracts and total renal TGF- were measured with ELISA assays using commercially available kits and the manufacturers’ instructions (R&D Systems, Minneapolis, MN; Ray Biotech, Norcross, GA). Serum TGF- was measured with a highly sensitive and specific bioassay as described previously (11).
mRNA levels that encoded TG (human) BMP-7 in several different organs from TG, nondiabetic control mice were assessed by RT-PCR using hBMP-7–specific primers (Table 1) and optimized PCR conditions avoiding co-amplification and recognition of endogenous, murine BMP-7. In whole-kidney RNA extracts from each mouse in the four groups, human and murine BMP-7 mRNA, respectively, was measured separately by competitive RT-PCR using selective primer sets (Table 1) and co-amplification of 18S rRNA as internal standard. Expression of transcription factor inhibitor of differentiation-1 (Id-1), plasminogen activator inhibitor-1 (PAI-1), 
2-chain of collagen I, and fibronectin also was assessed by competitive RT-PCR using mouse-specific primers (Table 1).
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Levels of phosphorylated Smad2/3 and Smad1/5 were assessed by Western blot analysis of 50 µg of whole-kidney protein extracts per lane. After electrophoretic separation and transfer onto nitrocellulose, membranes were incubated with anti-pSmad2/3 or anti-pSmad1/5 (Santa Cruz Biotechnology, Santa Cruz, CA) and appropriate horseradish peroxidase–conjugated second antibodies. Bands were visualized with chemiluminescence. Stripped membranes were reblotted with anti-GAPDH for loading control.
Total acid-soluble renal collagen was measured in frozen samples that were homogenized in 0.5 M acetic acid (50 µl/mg wet wt) and extracted on ice for 24 h. Samples were cleared by centrifugation. The collagen concentration in the extracts was measured in duplicate with a sircol dye precipitation method and collagen type I as standard using a commercially available kit (Biocolor Ltd., Newtonabbey, Northern Ireland, UK).
The activity of matrix metalloproteases/gelatinases was examined by gelatin zymography and with a quantitative activity assay. Zymography was performed on renal tissue extracts that were electrophoretically separated in SDS-PAGE gels (25 µg/ln) that contained 0.1% gelatin. Gels were incubated in 2.5% Triton X-100 in water to remove SDS and then incubated in buffer (50 mM Tris-HCl [pH 7.5], 200 mM NaCl, 5 mM CaCl2, and 0.02% Brij-35) for 30 h at 37°C. Gels then were stained with 0.5% Coomassie Blue G250 in water that contained 30% methanol and 10% glacial acetic acid and then destained in the same but dye-free solution. Semiquantitative data were obtained by densitometry. Total collagenase activity also was measured fluorometrically in kidney extracts that were diluted to 2 µg/µl using fluorescein-labeled gelatin as substrate and following the kit’s manufacturer’s instructions (EnzCheck; Molecular Probes, Eugene, OR).
Assessment of Podocyte Number and Glomerular and Interstitial Fibrosis
Podocytes were visualized in 4-µm kidney sections by immunofluorescence with anti–WT-1 (Santa Cruz Biotechnology) in 3% BSA/PBS for 16 h at 4°C after blocking with 10% normal serum. Nephrin was assessed by immunofluorescence with guinea pig polyclonal anti-nephrin antibody (Research Diagnostics Inc., Flanders, NJ). Slides then were incubated with fluorescein-conjugated second antibody. Quantification of WT-1–positive podocytes and of nephrin was performed by digital histomorphometry. Fifty glomeruli in each mouse were microphotographed in a Nikon Eclipse E400 microscope with a Nikon DXM1200 digital camera. In each glomerulus, the number of WT-1–positive podocytes was counted, and the color-specific pixel number reflecting nephrin was counted with Adobe Photoshop 6.0 software (Adobe Systems, San Jose, CA) and recorded as a fraction of the cross-sectional area of the glomerulus. Podocyte proliferation activity was assessed by double staining of sections with monoclonal anti–proliferating cell nuclear antigen (PCNA; Santa Cruz Biotechnology), biotinylated anti-mouse IgG (Vector Laboratories, Burlingame, CA), and Alexa Fluor 488–conjugated streptavidin (Molecular Probes) followed by staining with rabbit anti–WT-1 and Alexa Fluor 568–conjugated anti-rabbit IgG (Molecular Probes). Double-positive cells were counted in 50 glomerular cross-sections in each mouse.
Glomerular fibrosis was examined in 50 glomerular cross-sections of trichrome-stained slides and defined as the relative area of blue-stained collagens. Interstitial collagen was assessed in 20 nonoverlapping cortical interstitial high-power fields in each sample, and the pixel number of blue-stained collagen was counted.
Statistical Analyses
Group data are expressed as mean ± SE. Group comparisons were performed with ANOVA followed by Newman-Keuls multicomparison test. Statistical significance of differences between group means was defined at a probability of <5% (P < 0.05).
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Transgenic BMP-7 Does Not Affect TGF- Levels
Fibrogenesis in diabetic nephropathy has been shown in different laboratories to be TGF- driven, at least in part. In these studies, total TGF- levels were measured in kidney lysates and sera by ELISA and bioassay, respectively. In diabetic mice, renal TGF- levels tended to be elevated already at 4 wk and rose progressively further during the subsequent 48 wk; serum TGF- levels also were elevated in diabetic mice (Figure 5). TGF- was not affected by TG–BMP-7, consistent with the previous finding that BMP-7 does not regulate TGF- levels (4).
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Activities signaling (Figure 6c). Phosphorylation of BMP-signaling substrates Smad1/5 was increased in TG mouse kidney, indicative of increased bioactivity of the transgene-driven BMP-7.
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through Smad2/3-responsive promoter elements. Thus, the expression ratio of Id-1/PAI-1 can be used as an integrative measure for the renal activities of BMP-7 and TGF- in the context of these studies (13). Id-1 is expressed primarily in the glomerular and peritubular capillary endothelium, and its levels are visibly decreased in diabetic WT mice compared with nondiabetic WT animals (Figure 6a). The BMP-7 transgene raises Id-1 levels in nondiabetic mice; although induction of diabetes in BMP-7–TG mice lowers Id-1 expression, levels are still comparable to those seen in WT control mice and greater compared with WT diabetic mice. In WT mice, the diabetic state causes a significant decrease in Id-1 mRNA levels by 27 ± 4% and an increase in PAI-1 mRNA levels by 34 ± 5% at 16 wk compared with nondiabetic WT controls, leading to a substantial decrease in the Id-1/PAI-1 ratio (Figure 6b). In BMP-7–TG mice that were not diabetic, Id-1 mRNA levels were increased by 46 ± 8% compared with nondiabetic WT-Co, resulting in a substantial increase in the Id-1/PAI-1 ratio (Figure 6b). The BMP-7 transgene in diabetic mice maintains the Id-1/PAI-1 ratio at normal WT-Co levels and prevents the decrease in this ratio below baseline levels that was caused by the diabetic state in WT mice that did not express the BMP-7 transgene (Figure 6b). Although neither Smad1/5 phosphorylation nor Id-1 transcriptional upregulation is a specific effect of BMP-7 compared with other BMP, in concert and in the context of these studies, these findings can serve as indications for bioactivity of the transgene-derived BMP-7.
Transgenic BMP-7 Ameliorates Renal Fibrogenesis in Diabetes
Total acid–extracted collagen was increased at 52 wk compared with 4 wk in kidneys from all mice, including WT and BMP-7–TG, nondiabetic controls. In nondiabetic mice, total renal collagen increased late, after 16 wk (Figure 7a). In diabetic mice, total renal collagen was increased already at 16 wk, but subsequent increases were blunted in diabetic animals that expressed the BMP-7 transgene (Figure 7a). At 52 wk, the mRNA encoding the 2-chain of collagen type I or fibronectin were especially increased in WT diabetic mice, on average by 70% and approximately 4.5-fold, respectively (P < 0.05), compared with WT controls, and these diabetes-induced rises were virtually quantitatively prevented by the BMP-7 transgene (Figure 7, c and d).
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In WT mice, diabetes reduced renal matrix metalloprotease-1 (MMP2) and MMP9 activity at 1 yr, on average by 44 and 46%, respectively, compared with nondiabetic controls (P < 0.05 for each comparison). TG–BMP-7 per se had no effect on the activity of these two proteases; in BMP-7–TG mice with superimposed diabetes for 1 yr, the decrease in MMP2 and MMP9 activity was nominally less than in WT diabetic animals, on average 22 and 20%, respectively, but statistically not different from the decrease in WT diabetic mice. Total renal collagenase activity at 1 yr was substantially decreased in WT diabetic mice and tended to decrease less in TG mice with diabetes, albeit the difference between these two groups of animals was statistically indifferent (Figure 8).
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Transgenic BMP-7 Ameliorates Renal Functional Deterioration in Diabetes
Glomerular proteinuria (microalbuminuria) is an early functional hallmark of diabetic glomerulopathy. Diabetic WT as well as BMP-7–TG mice developed onset of albuminuria at approximately 10 to 16 wk of diabetes, which progressed subsequently. However, albuminuria worsened much more steeply in WT compared with TG mice with diabetes (Figure 10), and after 1 yr, the difference was approximately 4.5-fold. In contrast to nondiabetic WT and TG controls, both groups of diabetic mice were modestly azotemic at 1 yr (i.e., had elevated blood urea nitrogen [Figure 10]). This likely reflects prerenal azotemia given osmotic diuresis from hyperglycemia in these mice. Serum creatinine levels also tended to be moderately elevated in diabetic mice, reaching statistical significance only in diabetic WT mice but not in the group of diabetic mice that expressed the transgene. This rise in serum creatinine is indicative of renal insufficiency, perhaps as a result of diabetic nephropathy in addition to some degree of prerenal azotemia. Nevertheless, the BMP-7 transgene seems to protect renal functional integrity.
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Discussion |
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is a major mediator of diabetic renal fibrogenesis (18). Several pieces of experimental evidence indicate that BMP-7 reduces the fibrogenic activity of TGF- (4–7,19). Early findings in diabetic renal disease include dropout of podocytes and onset of albuminuria. In streptozotocin-induced diabetic nephropathy in rats, reduced renal expression of BMP-7 predates onset of these and other abnormalities, and exogenous, pharmacologic therapy with human recombinant BMP-7 has been shown to provide renal benefit (6,8). Findings from these studies suggest that the decrease in endogenous renal BMP-7 early in the course of diabetes contributes significantly to onset of diabetic nephropathy, perhaps by losing some of the counterbalance to the increased TGF- activity. In these studies, we tested the hypothesis that prevention of the loss by transcriptional downregulation of endogenous BMP-7 especially in glomerular podocytes early in diabetes by means of a selectively upregulated PEPCK-driven BMP-7 transgene would maintain renal and podocyte BMP-7 levels and preserve renal functional and structural integrity during diabetes. PEPCK is a rate-limiting enzyme that regulates gluconeogenesis. It is expressed in diverse tissues but not ubiquitously; in the kidney, strongest expression has been described in proximal tubules (20) but also in podocytes, as shown in these studies.
The rat PEPCK promoter has been used to regulate transgene expression of other proteins, including TGF- and human growth hormone in mice (9,21). Levels of PEPCK promoter transgene expression in various tissues can differ substantially. Reasons for these differences in transgene expression may include environmental factors and genetic background of the animals; moreover, transgene integration sites are random with substantial effects on expression efficiency (22). In these studies, we demonstrate expression of the PEPCK enzyme and the BMP-7–transgene in glomeruli, specifically podocytes, by RT-PCR and immunofluorescence microscopy, respectively. In conjunction with the seemingly very low circulating BMP-7 levels as indicated by the negative ELISA, these findings indicate that local expression of the BMP-7 transgene in podocytes accounts for the glomeruloprotective effects in diabetes.
Diabetes not only lowers renal BMP-7 levels but also decreases BMP-7 activity as illustrated by the reduction in renal pSmad1/5 levels and Id-1 and the Id-1/PAI-1 expression ratio. Id proteins are dominant negative inhibitors of basic helix-loop-helix transcription factors that play important roles in phenotype regulation of some cells. Whether Id-1 somehow contributes to reduce the onset and the progression of diabetic nephropathy by BMP-7 is unknown. Previous in vitro studies have shown that BMP-7–induced Smad5 reduces Smad2/3 signaling downstream of TGF- and, hence, lowers TGF-–dependent profibrogenic events in cultured cells (4,7). Evidence of this previous in vitro finding also is seen in these in vivo studies: The BMP-7 transgene leads to elevated renal levels of phosphorylated Smad1/5 and moderately reduced pSmad2/3 levels (Figure 6c) without affecting renal TGF- (Figure 5). In addition to reduced expression and levels of fibrosis-associated extracellular matrix proteins in glomeruli and the cortical interstitium, maintenance of BMP-7 in podocytes improves podocyte survival, which may account for lesser albuminuria in diabetic mice that express the BMP-7 transgene compared with their WT counterparts. BMP-7 may be a survival factor for podocytes as it is for neuronal cells (23). Given that TGF- reduces survival and increases apoptosis in podocytes through mechanisms that involve TGF-–induced Smad7, this beneficial effect of BMP-7 also may be explained by its antagonism to effects of TGF- (24).
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Conclusion |
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but reduces early accumulation of collagens and fibronectin and maintains renal collagenase activity, consistent with a TGF- activity–opposing action. Moreover, transgenic BMP-7 preserves podocyte number and lessens albuminuria, suggesting functions of endogenous BMP-7 as a podocyte survival factor. The loss of endogenous renal BMP-7 that has been observed in early diabetes in rodents contributes to diabetic nephropathy, and its prevention is beneficial.
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Acknowledgments |
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We appreciate the help of Paul Fu, PhD, in measuring serum blood urea nitrogen and creatinine levels. The assistance and the advice of the staff at the William Steers Biologic Resource Center at LABioMed in the animal maintenance also are greatly appreciated.
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, BMP-7–TG mice with diabetes (TG-DM); 
, WT diabetic mice (WT-DM); 
, BMP-7–TG, nondiabetic controls (TG-Co); 
, WT, nondiabetic controls (WT-Co). *P < 0.05 versus WT-Co.
