Insulin signaling to the glomerular podocyte is critical for normal kidney function.
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.
Welsh
Gavin I
GI
Academic Renal Unit, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK.
Hale
Lorna J
LJ
Academic Renal Unit, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK.
Eremina
Vera
V
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1X5, Canada.
Jeansson
Marie
M
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1X5, Canada.
Maezawa
Yoshiro
Y
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1X5, Canada.
Lennon
Rachel
R
Academic Renal Unit, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK.
Pons
Deborah A
DA
Academic Renal Unit, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK.
Owen
Rachel J
RJ
School of Physics, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK.
Satchell
Simon C
SC
Academic Renal Unit, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK.
Miles
Mervyn J
MJ
School of Physics, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK.
Caunt
Christopher J
CJ
Department of Molecular Pharmacology, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK.
McArdle
Craig A
CA
Department of Molecular Pharmacology, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK.
Pavenstädt
Hermann
H
Department of Internal Medicine D, Nephrology and Hypertension, University Clinics Muenster, Muenster 48149, Germany.
Tavaré
Jeremy M
JM
School of Biochemistry, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK.
Herzenberg
Andrew M
AM
Department of Pathology, University Health Network and University of Toronto, Ontario M5G 2C4, Canada.
Kahn
C Ronald
CR
Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA.
Mathieson
Peter W
PW
Academic Renal Unit, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK.
Quaggin
Susan E
SE
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1X5, Canada.
Saleem
Moin A
MA
Academic Renal Unit, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK.
Coward
Richard J M
RJM
Academic Renal Unit, School of Clinical Sciences, University of Bristol, Bristol BS8 1TH, UK; Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1X5, Canada. Electronic address: richard.coward@bristol.ac.uk.
D000818:Animals; D003928:Diabetic Nephropathies; D007328:Insulin / Q000502:physiology*; D007668:Kidney / Q000502:physiology*; D007678:Kidney Glomerulus / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D050199:Podocytes / Q000502:physiology*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D020928:Mitogen-Activated Protein Kinases