Insulin signaling to the glomerular podocyte is critical for normal kidney function

Gavin I. Welsh; Lorna J. Hale; Vera Eremina; Marie Jeansson; Yoshiro Maezawa; Rachel Lennon; Deborah A. Pons; Rachel J. Owen; Simon C. Satchell; Mervyn J. Miles; Christopher J. Caunt; Craig A. McArdle; Hermann Pavenstädt; Jeremy M. Tavaré; Andrew M. Herzenberg; C. Ronald Kahn; Peter W. Mathieson; Susan E. Quaggin; Moin A. Saleem; Richard J M Coward

doi:10.1016/j.cmet.2010.08.015

Insulin signaling to the glomerular podocyte is critical for normal kidney function

Gavin I. Welsh, Lorna J. Hale, Vera Eremina, Marie Jeansson, Yoshiro Maezawa, Rachel Lennon, Deborah A. Pons, Rachel J. Owen, Simon C. Satchell, Mervyn J. Miles, Christopher J. Caunt, Craig A. McArdle, Hermann Pavenstädt, Jeremy M. Tavaré, Andrew M. Herzenberg, C. Ronald Kahn, Peter W. Mathieson, Susan E. Quaggin, Moin A. Saleem, Richard J M Coward

Medicine, Nephrology Division

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

394 Scopus citations

Abstract

Diabetic nephropathy (DN) is the leading cause of renal failure in the world. It is characterized by albuminuria and abnormal glomerular function and is considered a hyperglycemic "microvascular" complication of diabetes, implying a primary defect in the endothelium. However, we have previously shown that human podocytes have robust responses to insulin. To determine whether insulin signaling in podocytes affects glomerular function in vivo, we generated mice with specific deletion of the insulin receptor from their podocytes. These animals develop significant albuminuria together with histological features that recapitulate DN, but in a normoglycemic environment. Examination of "normal" insulin-responsive podocytes in vivo and in vitro demonstrates that insulin signals through the MAPK and PI3K pathways via the insulin receptor and directly remodels the actin cytoskeleton of this cell. Collectively, this work reveals the critical importance of podocyte insulin sensitivity for kidney function.

Original language	English (US)
Pages (from-to)	329-340
Number of pages	12
Journal	Cell Metabolism
Volume	12
Issue number	4
DOIs	https://doi.org/10.1016/j.cmet.2010.08.015
State	Published - Oct 6 2010

Funding

R.J.M.C. and L.J.H. are supported by the Medical Research Council (grant number G0501901). The majority of the work presented here was funded by this grant. R.L. and S.C.S. are supported by the Wellcome trust. A.M.H. was supported by Canadian Diabetes Association Operating Grant #300349. Some of this work was supported by a grant awarded by North Bristol NHS Trust. We would like to thank Doug Holmyard, who processed the electron microscopic pictures; Ken Harpal, who prepared the renal histology; and Dionne White, who FACS sorted the glomerular cells. This work is dedicated to the brilliant Andrew Herzenberg (1971\u20132010), who was a major driving force within this project.

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cmet.2010.08.015

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Welsh, G. I., Hale, L. J., Eremina, V., Jeansson, M., Maezawa, Y., Lennon, R., Pons, D. A., Owen, R. J., Satchell, S. C., Miles, M. J., Caunt, C. J., McArdle, C. A., Pavenstädt, H., Tavaré, J. M., Herzenberg, A. M., Kahn, C. R., Mathieson, P. W., Quaggin, S. E., Saleem, M. A., & Coward, R. J. M. (2010). Insulin signaling to the glomerular podocyte is critical for normal kidney function. Cell Metabolism, 12(4), 329-340. https://doi.org/10.1016/j.cmet.2010.08.015

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title = "Insulin signaling to the glomerular podocyte is critical for normal kidney function",

abstract = "Diabetic nephropathy (DN) is the leading cause of renal failure in the world. It is characterized by albuminuria and abnormal glomerular function and is considered a hyperglycemic {"}microvascular{"} complication of diabetes, implying a primary defect in the endothelium. However, we have previously shown that human podocytes have robust responses to insulin. To determine whether insulin signaling in podocytes affects glomerular function in vivo, we generated mice with specific deletion of the insulin receptor from their podocytes. These animals develop significant albuminuria together with histological features that recapitulate DN, but in a normoglycemic environment. Examination of {"}normal{"} insulin-responsive podocytes in vivo and in vitro demonstrates that insulin signals through the MAPK and PI3K pathways via the insulin receptor and directly remodels the actin cytoskeleton of this cell. Collectively, this work reveals the critical importance of podocyte insulin sensitivity for kidney function.",

author = "Welsh, {Gavin I.} and Hale, {Lorna J.} and Vera Eremina and Marie Jeansson and Yoshiro Maezawa and Rachel Lennon and Pons, {Deborah A.} and Owen, {Rachel J.} and Satchell, {Simon C.} and Miles, {Mervyn J.} and Caunt, {Christopher J.} and McArdle, {Craig A.} and Hermann Pavenst{\"a}dt and Tavar{\'e}, {Jeremy M.} and Herzenberg, {Andrew M.} and Kahn, {C. Ronald} and Mathieson, {Peter W.} and Quaggin, {Susan E.} and Saleem, {Moin A.} and Coward, {Richard J M}",

note = "Funding Information: R.J.M.C. and L.J.H. are supported by the Medical Research Council (grant number G0501901). The majority of the work presented here was funded by this grant. R.L. and S.C.S. are supported by the Wellcome trust. A.M.H. was supported by Canadian Diabetes Association Operating Grant #300349. Some of this work was supported by a grant awarded by North Bristol NHS Trust. We would like to thank Doug Holmyard, who processed the electron microscopic pictures; Ken Harpal, who prepared the renal histology; and Dionne White, who FACS sorted the glomerular cells. This work is dedicated to the brilliant Andrew Herzenberg (1971–2010), who was a major driving force within this project. ",

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Welsh, GI, Hale, LJ, Eremina, V, Jeansson, M, Maezawa, Y, Lennon, R, Pons, DA, Owen, RJ, Satchell, SC, Miles, MJ, Caunt, CJ, McArdle, CA, Pavenstädt, H, Tavaré, JM, Herzenberg, AM, Kahn, CR, Mathieson, PW, Quaggin, SE, Saleem, MA & Coward, RJM 2010, 'Insulin signaling to the glomerular podocyte is critical for normal kidney function', Cell Metabolism, vol. 12, no. 4, pp. 329-340. https://doi.org/10.1016/j.cmet.2010.08.015

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T1 - Insulin signaling to the glomerular podocyte is critical for normal kidney function

AU - Welsh, Gavin I.

AU - Hale, Lorna J.

AU - Eremina, Vera

AU - Jeansson, Marie

AU - Maezawa, Yoshiro

AU - Lennon, Rachel

AU - Pons, Deborah A.

AU - Owen, Rachel J.

AU - Satchell, Simon C.

AU - Miles, Mervyn J.

AU - Caunt, Christopher J.

AU - McArdle, Craig A.

AU - Pavenstädt, Hermann

AU - Tavaré, Jeremy M.

AU - Herzenberg, Andrew M.

AU - Kahn, C. Ronald

AU - Mathieson, Peter W.

AU - Quaggin, Susan E.

AU - Saleem, Moin A.

AU - Coward, Richard J M

N1 - Funding Information: R.J.M.C. and L.J.H. are supported by the Medical Research Council (grant number G0501901). The majority of the work presented here was funded by this grant. R.L. and S.C.S. are supported by the Wellcome trust. A.M.H. was supported by Canadian Diabetes Association Operating Grant #300349. Some of this work was supported by a grant awarded by North Bristol NHS Trust. We would like to thank Doug Holmyard, who processed the electron microscopic pictures; Ken Harpal, who prepared the renal histology; and Dionne White, who FACS sorted the glomerular cells. This work is dedicated to the brilliant Andrew Herzenberg (1971–2010), who was a major driving force within this project.

PY - 2010/10/6

Y1 - 2010/10/6

N2 - Diabetic nephropathy (DN) is the leading cause of renal failure in the world. It is characterized by albuminuria and abnormal glomerular function and is considered a hyperglycemic "microvascular" complication of diabetes, implying a primary defect in the endothelium. However, we have previously shown that human podocytes have robust responses to insulin. To determine whether insulin signaling in podocytes affects glomerular function in vivo, we generated mice with specific deletion of the insulin receptor from their podocytes. These animals develop significant albuminuria together with histological features that recapitulate DN, but in a normoglycemic environment. Examination of "normal" insulin-responsive podocytes in vivo and in vitro demonstrates that insulin signals through the MAPK and PI3K pathways via the insulin receptor and directly remodels the actin cytoskeleton of this cell. Collectively, this work reveals the critical importance of podocyte insulin sensitivity for kidney function.

AB - Diabetic nephropathy (DN) is the leading cause of renal failure in the world. It is characterized by albuminuria and abnormal glomerular function and is considered a hyperglycemic "microvascular" complication of diabetes, implying a primary defect in the endothelium. However, we have previously shown that human podocytes have robust responses to insulin. To determine whether insulin signaling in podocytes affects glomerular function in vivo, we generated mice with specific deletion of the insulin receptor from their podocytes. These animals develop significant albuminuria together with histological features that recapitulate DN, but in a normoglycemic environment. Examination of "normal" insulin-responsive podocytes in vivo and in vitro demonstrates that insulin signals through the MAPK and PI3K pathways via the insulin receptor and directly remodels the actin cytoskeleton of this cell. Collectively, this work reveals the critical importance of podocyte insulin sensitivity for kidney function.

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Insulin signaling to the glomerular podocyte is critical for normal kidney function

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ASJC Scopus subject areas

UN SDGs

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