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Abstract: SA-PO413

AdipoR1 Is Reduced in Glomeruli in Type 2 Diabetes and Its Depletion in Podocytes in Vitro Impairs Integrin β1 Trafficking, Focal Adhesion Assembly, and Cell Adhesion

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Lehtonen, Sanna H., Helsingin yliopisto Laaketieteellinen tiedekunta, Helsinki, Uusimaa, Finland
  • Schmotz, Constanze, Helsingin yliopisto Laaketieteellinen tiedekunta, Helsinki, Uusimaa, Finland
  • Tienari, Jukka Pekka, HUS-yhtyma, Helsinki, Uusimaa, Finland
  • Saleem, Moin, University of Bristol, Bristol, Bristol, United Kingdom
  • Pfeil, Katharina, Medizinische Universitat Graz, Graz, Steiermark, Austria
  • Bugger, Heiko, Medizinische Universitat Graz, Graz, Steiermark, Austria
  • Pietiläinen, Kirsi H., Helsingin yliopisto Laaketieteellinen tiedekunta, Helsinki, Uusimaa, Finland
  • Mirtti, Tuomas, Helsingin yliopisto Laaketieteellinen tiedekunta, Helsinki, Uusimaa, Finland
  • Lindfors, Sonja, Helsingin yliopisto Laaketieteellinen tiedekunta, Helsinki, Uusimaa, Finland
Background

Adiponectin signals via adiponectin receptors 1 and 2 (AdipoR1/2) but the role of AdipoR1 in podocyte injury, and the regulation of AdipoR1 expression, remain unknown.

Methods

We carried out immunohistochemical stainings of kidneys of AdipoR1-deficient mice or people with type 2 diabetes (T2D). We treated podocytes with sera from lean and obese people, knocked down AdipoR1 lentivirally and overexpressed miR-221-3p in podocytes. Analyses included integrin endocytosis, adhesion and apoptosis assays.

Results

AdipoR1 and its binding partner APPL are downregulated in glomeruli of people with T2D without kidney disease and reduced AdipoR1 correlates with lowered podocyte number. In cultured podocytes, treatment with sera from obese people and overexpression of miR-221-3p reduce AdipoR1 expression. Expression of miR-221-3p is higher in glomeruli of people with T2D in comparison to controls, and the glomerular expression of miR-221-3p inversely correlates with AdipoR1-positive area. In cultured AdipoR1-knockdown (AdipoR1-KD) podocytes and mice depleted of AdipoR1, CD2AP, P-cadherin and synaptopodin are downregulated. This is coupled with reduced survival signaling and enhanced apoptosis and inflammation. AdipoR1-KD leads to mislocalization of APPL and impaired endocytic trafficking of active integrin β1. Focal adhesion (FA) appearance changes to plaque-like in AdipoR1-KD cells, resulting in increased mean FA area and decreased total cellular number of FAs. The expression of Arp3, which controls FA morphology, is reduced upon AdipoR1 knockdown and the cells show reduced re-adhesion.

Conclusion

Diabetes-associated mir-221-3p reduces AdipoR1 expression in podocytes. Lowered expression level of AdipoR1 in podocytes increases apoptosis and inflammation, impairs trafficking of active integrin β1 and alters FAs and cell adhesion. These alterations may contribute to kidney disease development in T2D.