Integrin Trafficking, Fibronectin Architecture, and Glomerular Injury upon AdipoR1 Depletion
Sonja Lindfors, Constanze Schmotz, Dominik Lewandowski, Annika Hau, Leena Saikko, Eero Lehtonen, Ville Majaniemi, Minna Karhe, Jette-Britt Naams, Harry Nisen, Jukka Tienari, Moin A. Saleem, Katharina Pfeil, Heiko Bugger, Kirsi H. Pietiläinen, Tuomas Mirtti, Krzysztof Palczewski, Sanna LehtonenBackground:
Deficiency of adiponectin and its downstream signaling may contribute to the pathogenesis of kidney injury in type 2 diabetes. Adiponectin activates intracellular signaling
Methods:
The expression of AdipoR1 in the kidneys of people with type 2 diabetes and the expression of podocyte proteins or injury markers in the kidneys of AdipoR1-knockout (AdipoR1-KO) mice and immortalized AdipoR1-deficient human podocytes were investigated by immunohistochemistry and immunoblotting. The functional role of AdipoR1 was studied in AdipoR1-deficient podocytes by performing assays for apoptosis, cytokine secretion, mechanical stress, adhesion, and endocytic trafficking.
Results:
Glomerular AdipoR1 expression was lower in type 2 diabetes and associated kidney disease, correlating with higher BMI and podocyte loss. Male AdipoR1-KO mice showed typical signs of early diabetic kidney disease, including albuminuria, glomerular structural abnormalities, and lower expression of central podocyte proteins; females were less affected. Podocyte apoptosis increased in female and male AdipoR1-KO mice and excessive podocyte loss, potentially due to detachment, was detected in males. AdipoR1 deficiency impaired the YAP-mediated mechanoresponse and induced accumulation of the extracellular matrix (ECM) protein fibronectin in the glomeruli
Conclusions:
AdipoR1 deficiency in mice resulted in the development of kidney injury predominantly in males. Mechanistically, AdipoR1 loss in podocytes impaired endocytosis of active integrin β1, which plausibly compromised focal adhesion dynamics, disturbed fibronectin matrix turnover, and hindered podocyte adhesion.