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Am J Physiol Renal Physiol 280: F19-F33, 2001;
0363-6127/01 $5.00
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Vol. 280, Issue 1, F19-F33, January 2001

BMP7 controls collecting tubule cell proliferation and apoptosis via Smad1-dependent and -independent pathways

Tino D. Piscione*, Tien Phan*, and Norman D. Rosenblum

Division of Nephrology, Program in Developmental Biology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8

Bone morphogenetic protein-7 (BMP7) controls ureteric bud and collecting duct morphogenesis in a dose-dependent manner (Piscione TD, Yager TD, Gupta IR, Grinfeld B, Pei Y, Attisono L, Wrana JL, and Rosenblum ND. Am J Physiol Renal Physiol 273: F961-F975, 1997). We defined cellular and molecular mechanisms underlying these effects in embryonic kidney explants and in the mIMCD-3 cell model of collecting tubule morphogenesis. Low-dose (0.25 nM) BMP7 significantly increased tubule number and cell proliferation. Similar to BMP2, high-dose (10 nM) BMP7 inhibited cell proliferation and stimulated apoptosis. To define molecular mechanisms, we identified signaling events downstream of BMP7. High-dose BMP7, but not low-dose BMP7, activated Smad1 in mIMCD-3 cells. Moreover, the inhibitory effects of high-dose BMP7 and BMP2, but not the stimulatory effects of low-dose BMP7, on tubulogenesis and cell proliferation were significantly reduced in mIMCD-3 cells stably expressing Smad1(Delta 458), a dominant negative mutant form of Smad1, but not in cells stably expressing wild-type Smad1. We conclude that BMP7 exerts dose-dependent effects on ureteric bud or collecting duct cell proliferation and apoptosis by signaling via Smad1-dependent and Smad1-independent pathways.

bone morphogenetic protein-7; renal collecting system; bone morphogenetic protein-2; branching morphogenesis

* T. D. Piscione and T. Phan contributed equally to this work.




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