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Renal Bone Morphogenetic Protein-7 Protects against Diabetic Nephropathy

Shinong Wang^*, Mark de Caestecker, Jeffrey Kopp, Grace Mitu^*, Janine LaPage^* and Raimund Hirschberg^*

^* 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.

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.

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