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| 2007 JASN IMPACT FACTOR 7.111 | HOME AUTHOR INFO EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP | |||
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| 2007 JASN IMPACT FACTOR 7.111 | HOME AUTHOR INFO EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP | |||
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Division of Nephrology, Harbor-UCLA Research and Education Institute, Inc., and UCLA, Torrance, California.
Correspondence to Dr. Raimund Hirschberg, Division of Nephrology, C-1-A, Harbor-UCLA Research & Education Institute, 1124 West Carson Street, Torrance, CA 90501. Phone: 310-222-3891; Fax: 310-782-1837; E-mail: rhirschberg{at}rei.edu
Abstract. Bone morphogenetic protein—7 (BMP7), a member of
the transforming growth factor—ß (TGF—ß) superfamily of
cytokines, is highly expressed in renal tubules and generally promotes
maintenance of epithelial phenotype. It was examined whether, during the
evolution of experimental diabetic nephropathy, the renal expression of BMP7
and BMP7 receptors declines, and the hypothesis that loss of BMP7 activity is
profibrogenic in proximal tubular cells was tested. Moreover, in
vitro studies in cultured proximal tubular cells were performed to
examine putative mechanisms that cause these changes. At 15 wk of
streptozotocin-induced diabetes, renal expression of BMP7 is declined by about
half, and it decreased further by 30 wk to <10% of timed controls. Renal
expression of the high-affinity BMP type II receptor and the type I receptor
Alk2 (activin receptor—like kinase-2) decreased. Alk3 tended to
decrease, but Alk6 remained unchanged. During the evolution of diabetic
nephropathy, the secreted BMP antagonist gremlin increased substantially. In
cultured tubular cells, TGF-ß reduced BMP7 and Alk3 expression and
increased gremlin but did not interrupt BMP7-induced activation of smad5 or
Erk1 and -2. In contrast, BMP7 did not alter TGF-ß expression.
Neutralization of endogenous BMP7 in cultured proximal tubular cells raised
the expression of fibronectin and tended to increase collagen
1 III mRNA levels. In conclusion, in experimental diabetic
nephropathy, renal tubular BMP7 and some of its receptors decreased and
gremlin, a secreted BMP antagonist, increased. Some, but not all, of these
changes are explained by increased TGF-ß. The loss of BMP7 activity
per se is profibrogenic in tubular cells.
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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673
