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BMP7 controls collecting tubule cell proliferation and apoptosis via Smad1-dependent and -independent pathways
T D Piscione1, T Phan, N D Rosenblum
1Division of Nephrology, Program in Developmental Biology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8.
Abstract:
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(Delta458), 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.
Insights
Bone morphogenetic protein-7 (BMP7) influences kidney collecting duct development differently based on dose. Low-dose BMP7 promotes cell growth, while high-dose BMP7 inhibits growth and triggers cell death via Smad1 pathways.
Area of Science:
- Nephrology
- Developmental Biology
- Molecular Biology
Background:
- Bone morphogenetic protein-7 (BMP7) is known to regulate kidney development.
- Understanding BMP7's precise role in collecting duct morphogenesis is crucial for developmental biology.
Purpose of the Study:
- To elucidate the dose-dependent cellular and molecular mechanisms of BMP7 in kidney collecting duct development.
- To investigate the role of Smad1 signaling in BMP7-mediated effects.
Main Methods:
- Utilized embryonic kidney explants and the mIMCD-3 cell line for collecting tubule morphogenesis studies.
- Administered varying doses of BMP7 (0.25 nM and 10 nM) to assess effects on cell proliferation and apoptosis.
- Analyzed Smad1 activation and utilized Smad1 dominant-negative mutants to define signaling pathways.
Main Results:
- Low-dose BMP7 (0.25 nM) significantly increased tubule number and cell proliferation.
- High-dose BMP7 (10 nM) inhibited cell proliferation and induced apoptosis, similar to BMP2.
- High-dose BMP7 activated Smad1, and its inhibitory effects were Smad1-dependent, while low-dose effects were not fully Smad1-dependent.
Conclusions:
- BMP7 exerts dose-dependent control over ureteric bud and collecting duct cell proliferation and apoptosis.
- BMP7 signaling involves both Smad1-dependent and Smad1-independent pathways in kidney development.