Renal bone morphogenetic protein-7 protects against diabetic nephropathy.
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-beta 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-beta 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.
Wang
Shinong
S
LABiomed, C-1-A, 1124 West Carson Street, Torrance, CA 90502, USA.
de Caestecker
Mark
M
Kopp
Jeffrey
J
Mitu
Grace
G
Lapage
Janine
J
Hirschberg
Raimund
R
D000818:Animals; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D005355:Fibrosis; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism; D007668:Kidney / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051898:Smad1 Protein / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D017395:Plasminogen Activator Inhibitor 1; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D016212:Transforming Growth Factor beta; D010729:Phosphoenolpyruvate Carboxykinase (GTP)