Contrasting consequences of podocyte insulin-like growth factor 1 receptor inhibition
Jennifer A. Hurcombe,
Fern Barrington,
Micol Marchetti,
Virginie M.S. Betin,
Emily E. Bowen,
Abigail C. Lay,
Lan Ni,
Lusyan Dayalan,
Robert J.P. Pope,
Paul T. Brinkkoetter,
Martin Holzenberger,
Gavin I. Welsh,
Richard J.M. Coward
Affiliations
Jennifer A. Hurcombe
Bristol Renal, University of Bristol, Bristol, UK
Fern Barrington
Bristol Renal, University of Bristol, Bristol, UK
Micol Marchetti
Bristol Renal, University of Bristol, Bristol, UK
Virginie M.S. Betin
Bristol Renal, University of Bristol, Bristol, UK
Emily E. Bowen
Bristol Renal, University of Bristol, Bristol, UK
Abigail C. Lay
Bristol Renal, University of Bristol, Bristol, UK
Lan Ni
Bristol Renal, University of Bristol, Bristol, UK
Lusyan Dayalan
Bristol Renal, University of Bristol, Bristol, UK
Robert J.P. Pope
Bristol Renal, University of Bristol, Bristol, UK
Paul T. Brinkkoetter
Department II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
Martin Holzenberger
Sorbonne University, INSERM, Paris, France
Gavin I. Welsh
Bristol Renal, University of Bristol, Bristol, UK
Richard J.M. Coward
Bristol Renal, University of Bristol, Bristol, UK; Corresponding author
Summary: Insulin signaling to the glomerular podocyte via the insulin receptor (IR) is critical for kidney function. In this study we show that near-complete knockout of the closely related insulin-like growth factor 1 receptor (IGF1R) in podocytes is detrimental, resulting in albuminuria in vivo and podocyte cell death in vitro. In contrast, partial podocyte IGF1R knockdown confers protection against doxorubicin-induced podocyte injury. Proteomic analysis of cultured podocytes revealed that while near-complete loss of podocyte IGF1R results in the downregulation of mitochondrial respiratory complex I and DNA damage repair proteins, partial IGF1R inhibition promotes respiratory complex expression. This suggests that altered mitochondrial function and resistance to podocyte stress depends on the level of IGF1R suppression, the latter determining whether receptor inhibition is protective or detrimental. Our work suggests that the partial suppression of podocyte IGF1R could have therapeutic benefits in treating albuminuric kidney disease.
