title: 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-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.
authors.affiliation: LABiomed, C-1-A, 1124 West Carson Street, Torrance, CA 90502, USA.
authors.forename: Shinong
authors.initials: S
authors.lastname: Wang
authors.forename: Mark
authors.initials: M
authors.lastname: de Caestecker
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kopp
authors.forename: Grace
authors.initials: G
authors.lastname: Mitu
authors.forename: Janine
authors.initials: J
authors.lastname: Lapage
authors.forename: Raimund
authors.initials: R
authors.lastname: Hirschberg
mesh_terms: 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
chemical_list: 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)