Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice

Mei Ding; Shiying Cui; Chengjin Li; Serge Jothy; Volker Haase; Brent M. Steer; Philip A. Marsden; Jeffrey Pippin; Stuart Shankland; Maria Pia Rastaldi; Clemens D. Cohen; Matthias Kretzler; Susan E. Quaggin

doi:10.1038/nm1460

Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice

Mei Ding, Shiying Cui, Chengjin Li, Serge Jothy, Volker Haase, Brent M. Steer, Philip A. Marsden, Jeffrey Pippin, Stuart Shankland, Maria Pia Rastaldi, Clemens D. Cohen, Matthias Kretzler, Susan E. Quaggin^*

^*Corresponding author for this work

Medicine, Nephrology Division

Research output: Contribution to journal › Article › peer-review

178 Scopus citations

Abstract

Rapidly progressive glomerulonephritis (RPGN) is a clinical syndrome characterized by loss of renal function within days to weeks and by glomerular crescents on biopsy. The pathogenesis of this disease is unclear, but circulating factors are believed to have a major role. Here, we show that deletion of the Von Hippel-Lindau gene (Vhlh) from intrinsic glomerular cells of mice is sufficient to initiate a necrotizing crescentic glomerulonephritis and the clinical features that accompany RPGN. Loss of Vhlh leads to stabilization of hypoxia-inducible factor α subunits (HIFs). Using gene expression profiling, we identified de novo expression of the HIF target gene Cxcr4 (ref. 3) in glomeruli from both mice and humans with RPGN. The course of RPGN is markedly improved in mice treated with a blocking antibody to Cxcr4, whereas overexpression of Cxcr4 alone in podocytes of transgenic mice is sufficient to cause glomerular disease. Collectively, these results indicate an alternative mechanism for the pathogenesis of RPGN and glomerular disease in an animal model and suggest novel molecular pathways for intervention in this disease.

Original language	English (US)
Pages (from-to)	1081-1087
Number of pages	7
Journal	Nature Medicine
Volume	12
Issue number	9
DOIs	https://doi.org/10.1038/nm1460
State	Published - Sep 2006

Funding

The authors thank D. Vukasovic for secretarial assistance and the Centre for Modelling Human Diseases for biochemical assays in the mice. We also thank B. Pressler (University of North Carolina at Chapel Hill) for performing ANCA assays, Y. Wang (Samuel Lunenfeld Research Institute) for help in LCM isolation, S. Peiper (Institute of Molecular Medicine and Genetics, Georgia) for providing the constitutively active Cxcr4 constructs, V. Eremina for technical assistance, K. Kamel (St. Michael’s Hospital, Toronto) and D. Cattran (Toronto Hospital) for critically reviewing the manuscript. S.E.Q. is the recipient of a Canada Research Chair Tier II, and a Premier’s Research of Excellence Award. This work was funded by Canadian Institute of Health Research grant MOP 77756, National Cancer Institute of Canada grant #16002 and Emerald Foundation grant (to S.E.Q.).

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1038/nm1460

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@article{564d7658f9c94b2b93b0e9c721bcd388,

title = "Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice",

abstract = "Rapidly progressive glomerulonephritis (RPGN) is a clinical syndrome characterized by loss of renal function within days to weeks and by glomerular crescents on biopsy. The pathogenesis of this disease is unclear, but circulating factors are believed to have a major role. Here, we show that deletion of the Von Hippel-Lindau gene (Vhlh) from intrinsic glomerular cells of mice is sufficient to initiate a necrotizing crescentic glomerulonephritis and the clinical features that accompany RPGN. Loss of Vhlh leads to stabilization of hypoxia-inducible factor α subunits (HIFs). Using gene expression profiling, we identified de novo expression of the HIF target gene Cxcr4 (ref. 3) in glomeruli from both mice and humans with RPGN. The course of RPGN is markedly improved in mice treated with a blocking antibody to Cxcr4, whereas overexpression of Cxcr4 alone in podocytes of transgenic mice is sufficient to cause glomerular disease. Collectively, these results indicate an alternative mechanism for the pathogenesis of RPGN and glomerular disease in an animal model and suggest novel molecular pathways for intervention in this disease.",

author = "Mei Ding and Shiying Cui and Chengjin Li and Serge Jothy and Volker Haase and Steer, {Brent M.} and Marsden, {Philip A.} and Jeffrey Pippin and Stuart Shankland and Rastaldi, {Maria Pia} and Cohen, {Clemens D.} and Matthias Kretzler and Quaggin, {Susan E.}",

note = "Funding Information: The authors thank D. Vukasovic for secretarial assistance and the Centre for Modelling Human Diseases for biochemical assays in the mice. We also thank B. Pressler (University of North Carolina at Chapel Hill) for performing ANCA assays, Y. Wang (Samuel Lunenfeld Research Institute) for help in LCM isolation, S. Peiper (Institute of Molecular Medicine and Genetics, Georgia) for providing the constitutively active Cxcr4 constructs, V. Eremina for technical assistance, K. Kamel (St. Michael{\textquoteright}s Hospital, Toronto) and D. Cattran (Toronto Hospital) for critically reviewing the manuscript. S.E.Q. is the recipient of a Canada Research Chair Tier II, and a Premier{\textquoteright}s Research of Excellence Award. This work was funded by Canadian Institute of Health Research grant MOP 77756, National Cancer Institute of Canada grant #16002 and Emerald Foundation grant (to S.E.Q.).",

year = "2006",

month = sep,

doi = "10.1038/nm1460",

language = "English (US)",

volume = "12",

pages = "1081--1087",

journal = "Nature Medicine",

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T1 - Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice

AU - Ding, Mei

AU - Cui, Shiying

AU - Li, Chengjin

AU - Jothy, Serge

AU - Haase, Volker

AU - Steer, Brent M.

AU - Marsden, Philip A.

AU - Pippin, Jeffrey

AU - Shankland, Stuart

AU - Rastaldi, Maria Pia

AU - Cohen, Clemens D.

AU - Kretzler, Matthias

AU - Quaggin, Susan E.

N1 - Funding Information: The authors thank D. Vukasovic for secretarial assistance and the Centre for Modelling Human Diseases for biochemical assays in the mice. We also thank B. Pressler (University of North Carolina at Chapel Hill) for performing ANCA assays, Y. Wang (Samuel Lunenfeld Research Institute) for help in LCM isolation, S. Peiper (Institute of Molecular Medicine and Genetics, Georgia) for providing the constitutively active Cxcr4 constructs, V. Eremina for technical assistance, K. Kamel (St. Michael’s Hospital, Toronto) and D. Cattran (Toronto Hospital) for critically reviewing the manuscript. S.E.Q. is the recipient of a Canada Research Chair Tier II, and a Premier’s Research of Excellence Award. This work was funded by Canadian Institute of Health Research grant MOP 77756, National Cancer Institute of Canada grant #16002 and Emerald Foundation grant (to S.E.Q.).

PY - 2006/9

Y1 - 2006/9

N2 - Rapidly progressive glomerulonephritis (RPGN) is a clinical syndrome characterized by loss of renal function within days to weeks and by glomerular crescents on biopsy. The pathogenesis of this disease is unclear, but circulating factors are believed to have a major role. Here, we show that deletion of the Von Hippel-Lindau gene (Vhlh) from intrinsic glomerular cells of mice is sufficient to initiate a necrotizing crescentic glomerulonephritis and the clinical features that accompany RPGN. Loss of Vhlh leads to stabilization of hypoxia-inducible factor α subunits (HIFs). Using gene expression profiling, we identified de novo expression of the HIF target gene Cxcr4 (ref. 3) in glomeruli from both mice and humans with RPGN. The course of RPGN is markedly improved in mice treated with a blocking antibody to Cxcr4, whereas overexpression of Cxcr4 alone in podocytes of transgenic mice is sufficient to cause glomerular disease. Collectively, these results indicate an alternative mechanism for the pathogenesis of RPGN and glomerular disease in an animal model and suggest novel molecular pathways for intervention in this disease.

AB - Rapidly progressive glomerulonephritis (RPGN) is a clinical syndrome characterized by loss of renal function within days to weeks and by glomerular crescents on biopsy. The pathogenesis of this disease is unclear, but circulating factors are believed to have a major role. Here, we show that deletion of the Von Hippel-Lindau gene (Vhlh) from intrinsic glomerular cells of mice is sufficient to initiate a necrotizing crescentic glomerulonephritis and the clinical features that accompany RPGN. Loss of Vhlh leads to stabilization of hypoxia-inducible factor α subunits (HIFs). Using gene expression profiling, we identified de novo expression of the HIF target gene Cxcr4 (ref. 3) in glomeruli from both mice and humans with RPGN. The course of RPGN is markedly improved in mice treated with a blocking antibody to Cxcr4, whereas overexpression of Cxcr4 alone in podocytes of transgenic mice is sufficient to cause glomerular disease. Collectively, these results indicate an alternative mechanism for the pathogenesis of RPGN and glomerular disease in an animal model and suggest novel molecular pathways for intervention in this disease.

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JO - Nature Medicine

JF - Nature Medicine

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ER -

Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice

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