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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

419 Citations (Scopus)

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.

[See paper for graphical abstract]

Original language	English
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
Publication status	Published - 6 Oct 2010

Bibliographical note

Publisher Copyright:
© 2010 Elsevier Inc. All rights reserved.

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

Animals
Diabetic Nephropathies
Insulin
Kidney
Kidney Glomerulus
Mice
Mice, Knockout
Mitogen-Activated Protein Kinases
Phosphatidylinositol 3-Kinases
Podocytes
Receptor, Insulin
Signal Transduction

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10.1016/j.cmet.2010.08.015

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MRC Award
Coward , R. J. M. (Principal Investigator)
1/12/06 → 1/12/10
Project: Research

Cite this

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. [See paper for graphical abstract] ",

keywords = "Animals, Diabetic Nephropathies, Insulin, Kidney, Kidney Glomerulus, Mice, Mice, Knockout, Mitogen-Activated Protein Kinases, Phosphatidylinositol 3-Kinases, Podocytes, Receptor, Insulin, Signal Transduction",

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year = "2010",

month = oct,

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doi = "10.1016/j.cmet.2010.08.015",

language = "English",

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journal = "Cell Metabolism",

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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

TY - JOUR

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

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. [See paper for graphical abstract]

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. [See paper for graphical abstract]

KW - Animals

KW - Diabetic Nephropathies

KW - Insulin

KW - Kidney

KW - Kidney Glomerulus

KW - Mice

KW - Mice, Knockout

KW - Mitogen-Activated Protein Kinases

KW - Phosphatidylinositol 3-Kinases

KW - Podocytes

KW - Receptor, Insulin

KW - Signal Transduction

U2 - 10.1016/j.cmet.2010.08.015

DO - 10.1016/j.cmet.2010.08.015

M3 - Article (Academic Journal)

C2 - 20889126

SN - 1550-4131

VL - 12

SP - 329

EP - 340

JO - Cell Metabolism

JF - Cell Metabolism

IS - 4

ER -

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

Abstract

Bibliographical note

UN SDGs

Keywords

Access to Document

Handle.net

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Projects

MRC Award

Cite this