Abstract: PO1692
Insulin-Like Growth Factor 1 Receptor (IGF1R) Suppression in the Glomerular Podocyte Has Beneficial and Detrimental Consequences Dependent on the Level of Inhibition
Session Information
- Podocyte Pathobiology: Basic Science Studies and Animal Models
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1204 Podocyte Biology
Authors
- Hurcombe, Jenny, University of Bristol, Bristol, Bristol, United Kingdom
- Barrington, Fern, University of Bristol, Bristol, Bristol, United Kingdom
- Betin, Virginie M. S., University of Bristol, Bristol, Bristol, United Kingdom
- Lay, Abigail Charlotte, University of Bristol, Bristol, Bristol, United Kingdom
- Dayalan, Lusyan, University of Bristol, Bristol, Bristol, United Kingdom
- Ni, Lan, University of Bristol, Bristol, Bristol, United Kingdom
- Brinkkoetter, Paul T., Uniklinik Koln, Koln, Nordrhein-Westfalen, Germany
- Holzenberger, Martin, INSERM, Paris, Île-de-France, France
- Welsh, Gavin Iain, University of Bristol, Bristol, Bristol, United Kingdom
- Coward, Richard, University of Bristol, Bristol, Bristol, United Kingdom
Background
Insulin signalling to the glomerular podocyte via the insulin receptor (IR) is known to be critical for normal kidney function. This study aimed to define the physiological importance of the closely related insulin-like growth factor 1 receptor (IGF1R) in podocytes.
Methods
Transgenic mice with conditional inactivation of podocyte IGF1R were generated to determine the effects of IGF1R suppression in vivo. In vitro, conditionally immortalised genetic IGF1R knockout and wild-type podocytes treated with the IGF1R inhibitor picropodophyllin (PPP) were characterised using global proteomic analysis.
Results
Transgenic mice with partial podocyte-specific IGF1R knockout, generated using conventional Cre recombinase, had no apparent basal renal phenotype but unexpectedly, were protected from doxorubicin-induced nephropathy. An additional mouse model using an epigenetically resistant podocyte Cre driver designed to increase receptor knockout efficiency, exhibited mild basal albuminuria by 24 weeks.
Our in vitro models revealed that the degree of IGF1R inhibition in the podocyte is important. Greater than 90% knockout caused ~50% cell death after 7 days and did not protect against doxorubicin-induced cell death whilst wild-type podocytes treated with PPP (partial inhibition) showed enhanced survival when stressed with doxorubicin.
Proteomic analysis revealed that near complete IGF1R suppression results in downregulation of mitochondrial respiratory complex I and DNA damage repair proteins whilst partial IGF1R inhibition promotes expression of respiratory complexes.
Conclusion
Altered mitochondrial function, impairment of DNA damage responses and resistance to oxidative stress in podocytes is dependent on the level of IGF1R suppression and determines whether receptor inhibition is protective or mildly detrimental.
Funding
- Government Support – Non-U.S.