Bone morphogenic protein-7 (BMP-7), a novel therapy for diabetic nephropathy11Professor Robert Chevalier served as a guest editor for this paper.

Wang, Song; Chen, Qing; Simon, Theodore C.; Strebeck, Frank; Chaudhary, Lala R.; Morrissey, Jeremiah J.; Liapis, Helen; Klahr, Saulo; Hruska, Keith A.

doi:10.1046/j.1523-1755.2003.00035.x

Cited by 213 publications

(63 citation statements)

References 33 publications

(21 reference statements)

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“…Its ongoing role in osteoblast function suggests a hormonal role, and circulating levels are detectable. BMP-7 expression is downregulated early in CRF (21)(22)(23), and the concept of CRF as a state of BMP-7 deficiency is supported by studies showing that therapy with BMP-7 is efficacious in several rodent models of renal disease (21,(23)(24)(25)(26)(27). BMP-7 may also play a role in maintaining VSMC differentiation and preventing transdifferentiation of VSMC into an osteoblast phenotype.…”

mentioning

confidence: 78%

BMP-7 Is an Efficacious Treatment of Vascular Calcification in a Murine Model of Atherosclerosis and Chronic Renal Failure

Davies

Lund²,

Hruska³

2003

Journal of the American Society of Nephrology

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197

162

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Abstract. Chronic renal failure is complicated by high cardiovascular mortality. One key contributor to this mortality is vascular calcification, for which no therapy currently exists. Bone morphogenetic protein 7 is an essential renal morphogen that maintains renal tubular differentiation in the adult and is downregulated in renal failure. Several studies have demonstrated its efficacy in treating various renal diseases in rodents, and it was hypothesized that it would also be an effective treatment of vascular calcification in this setting. Uremia was imposed on LDL receptor null mice (a model of atherosclerosis), which were then treated with bone morphogenetic protein 7 for 15 wk. Uremic animals had increased vascular calcification by histology and chemical analysis. Calcification in treated animals was similar to or less than non-uremic control animals. Cells exhibiting an osteoblast-like phenotype in the vessel wall may be important in the etiology of vascular calcification. Expression of osteocalcin was assessed as a marker of osteoblastic function, and it is shown that it is increased in untreated uremic animals but downregulated to levels similar to non-uremic control animals with treatment.

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mentioning

confidence: 78%

BMP-7 Is an Efficacious Treatment of Vascular Calcification in a Murine Model of Atherosclerosis and Chronic Renal Failure

Davies

Lund²,

Hruska³

2003

Journal of the American Society of Nephrology

Self Cite

197

162

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“…Antifibrotic action of BMP-7 is mediated via direct antagonism of TGF-␤1 signaling (12,28,29). Previous studies suggest a therapeutic benefit for rhBMP-7 in a rat model of STZ-induced diabetic glomerulosclerosis (which do not develop interstitial fibrosis) (30).…”

Section: Resultsmentioning

confidence: 99%

Renal Fibrosis and Glomerulosclerosis in a New Mouse Model of Diabetic Nephropathy and Its Regression by Bone Morphogenic Protein-7 and Advanced Glycation End Product Inhibitors

et al. 2007

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Diabetic nephropathy is currently the most common cause of end-stage renal disease (ESRD) in the western world. A mouse model for diabetic nephropathy that encompasses the salient features of this disease in the kidney is not available. Here, we report that CD1 mice, in contrast to inbred C57BL/6 and 129Sv strains, develop ESRD associated with prominent tubulointerstitial nephritis and fibrosis within 3 months and die because of diabetic complications by 6 -7 months after a single injection of streptozotocin. Histopathologic lesions observed in these mice mimic human diabetic nephropathy, including glomerular hypertrophy, diffuse glomerulosclerosis, tubular atrophy, interstitial fibrosis, and decreased renal excretory function. Next, we tested the therapeutic efficacy of bone morphogenic protein-7 (BMP-7) and inhibitors of advanced glycation end products (AGEs), aminoguanidine and pyridoxamine, to inhibit and regress the progression of renal disease in diabetic CD1 mice. We demonstrate that although aminoguanidine, pyridoxamine, and BMP-7 significantly inhibit glomerular lesions, BMP-7 is most effective in the inhibition of tubular inflammation and tubulointerstitial fibrosis in these mice. Collectively, our results report a new mouse model for diabetic nephropathy with prominent interstitial inflammation and fibrosis and the selective inhibition of diabetic kidney disease by AGE inhibitors and BMP-7.

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“…A number of studies have shown that TGF-␤ is an important factor in diabetic nephropathy progression through the use of knockout (KO) mouse models for the TGF-␤ type II receptor (9) (which binds TGF-␤1) and TGF-␤ blocking antibodies (10 -12). The investigation of other molecules involved in the regulation of TGF-␤ such as the antifibrogenic peptide bone morphogenic protein 7 (BMP7) (13), which counterbalances TGF-␤ activity and is downregulated in diabetes (14), have also shown efficacy as a strategy for reducing diabetic nephropathy progression (15). Although TGF-␤ is involved in the onset and progression of diabetic nephropathy, the nature of this role, particularly related to the onset of albuminuria, remains speculative.…”

mentioning

confidence: 99%

Evidence for a Role of Transforming Growth Factor (TGF)-β1 in the Induction of Postglomerular Albuminuria in Diabetic Nephropathy

et al. 2007

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Transforming growth factor-␤ (TGF-␤) has previously been implicated in the progression of diabetic nephropathy, including the onset of fibrosis and albuminuria. Here we report for the first time the use of a high-affinity TGF-␤1 binding molecule, the soluble human TGF-␤ type II receptor (sT␤RII.Fc), in the treatment of diabetic nephropathy in 12-week streptozotocin-induced diabetic Sprague-Dawley rats. In vitro studies using immortalized rat proximal tubule cells revealed that 50 pmol/l TGF-␤1 disrupted albumin uptake (P < 0.001 vs. control), an inhibition significantly reversed by the use of the sT␤RII.Fc (1,200 pmol/l). In vivo studies demonstrated that treatment with sT␤RII.Fc reduced urinary albumin excretion by 36% at 4 weeks, 59% at 8 weeks (P < 0.001), and 45% at 12 weeks (P < 0.01 for diabetic vs. treated). This was correlated with an increase in megalin expression (P < 0.05 for diabetic vs. treated) and a reduction in collagen IV expression following sT␤RII.Fc treatment (P < 0.001 for diabetic vs. treated). These changes occurred independently of changes in blood glucose levels. This study demonstrates that the sT␤RII.Fc is a potential new agent for the treatment of fibrosis and albuminuria in diabetic nephropathy and may reduce albuminuria by reducing TGF-␤1-induced disruptions of renal proximal tubule cell uptake of albumin. Diabetes 56:380 -388, 2007

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Bone morphogenic protein-7 (BMP-7), a novel therapy for diabetic nephropathy11Professor Robert Chevalier served as a guest editor for this paper.

Abstract: BMP-7 partially reversed diabetic-induced kidney hypertrophy, restoring GFR, urine albumin excretion, and glomerular histology toward normal. Restoration of BMP-7 expression was associated with a successful repair reaction and a reversal of the ill-fated injury response.

Cited by 213 publications

References 33 publications

BMP-7 Is an Efficacious Treatment of Vascular Calcification in a Murine Model of Atherosclerosis and Chronic Renal Failure

BMP-7 Is an Efficacious Treatment of Vascular Calcification in a Murine Model of Atherosclerosis and Chronic Renal Failure

Renal Fibrosis and Glomerulosclerosis in a New Mouse Model of Diabetic Nephropathy and Its Regression by Bone Morphogenic Protein-7 and Advanced Glycation End Product Inhibitors

Evidence for a Role of Transforming Growth Factor (TGF)-β1 in the Induction of Postglomerular Albuminuria in Diabetic Nephropathy

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