Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models.
Tubulointerstitial fibrosis is a hallmark feature of chronic renal injury. Specific therapies to control the progression of renal fibrosis toward end-stage renal failure are limited. Previous studies have demonstrated that expression of endogenous bone morphogenic protein-7 (BMP-7) is reduced in the kidneys of several inducible mouse models of acute and chronic renal disease and that administration of exogenous recombinant human BMP-7 (rhBMP-7) has a beneficial effect on kidney function. Here we report that treatment with rhBMP-7 leads to improved renal function, histology, and survival in mice deficient in the alpha3-chain of type IV collagen and MRL/MpJlpr/lpr lupus mice, two genetic models for chronic renal injury and fibrosis. Such therapeutic benefit is also associated with a significant decrease in the expression of profibrotic molecules, such as type I collagen and fibronectin, in renal fibroblasts. Additionally, rhBMP-7 induces expression of active matrix metalloproteinase-2, which is potentially important for removal of fibrotic matrix. Collectively, these studies provide further evidence for rhBMP-7 as an important bone-associated protein with protective function against renal pathology.
Zeisberg
Michael
M
Center for Matrix Biology, Department of Medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215, USA.
Bottiglio
Cindy
C
Kumar
Navin
N
Maeshima
Yohei
Y
Strutz
Frank
F
Müller
Gerhard A
GA
Kalluri
Raghu
R
D000818:Animals; D001324:Autoantigens / Q000235:genetics; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005355:Fibrosis; D006801:Humans; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008181:Lupus Nephritis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008817:Mice, Mutant Strains; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D016212:Transforming Growth Factor beta
D001324:Autoantigens; C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D024141:Collagen Type IV; D018696:Neuroprotective Agents; D016212:Transforming Growth Factor beta; C057112:type IV collagen alpha3 chain