Renal Bone Morphogenetic Protein-7 Protects against Diabetic Nephropathy

Abstract

Longstanding diabetes causes renal injury with early dropout of podocytes, albuminuria, glomerular and tubulointerstitial fibrosis, and progressive renal failure. The renal pathology seems to be driven, in part, by TGF-␤ 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.

Exogenous BMP-7 Facilitates the Recovery of Cardiac Function after Acute Myocardial Infarction through Counteracting TGF-<i>β</i>1 Signaling Pathway

“…Accumulated evidence suggested that BMP-7 signaling was beneficial to resolve established organ damage, especially renal and hepatic progressive fibrosis (Wang et al 2006;Sugimoto et al 2007;Zeisberg and Kalluri 2008). Of note, small peptide agonists of BMP-7 receptors have been developed to inhibit kidney inflammation, tissue damage, and fibrosis (Sugimoto et al 2007).…”

Gremlin1 preferentially binds to bone morphogenetic protein-2 (BMP-2) and BMP-4 over BMP-7

“…We and others have shown that Grem1 levels increase during DN whereas levels of BMP-7 decrease [33,46]. Strategies that stimulate BMP-7 signalling have been shown to attenuate renal fibrosis [5,[12][13][14][15][16][17], and reductions in Grem1 levels have a similar beneficial effect in mouse models of DN [32,37].…”

Osteogenic Protein-1 Overcomes Inhibition of Fracture Healing in the Diabetic Rat: A Pilot Study

“…Responding progenitor elements (stromal, periosteal, and perivascular cells) may retain their inductive response to BMPs, thereby overcoming an inhibitory environment [4]. Because BMP receptor II is downregulated in diabetes mellitus [33], it is possible treatment of a diabetic fracture with exogenous BMP may stimulate expression of BMP receptors [35]. It also is possible administration of exogenous BMP may compensate for the delay in Type X collagen expression and associated chondrocyte maturation observed in diabetes [16].…”