Integrin Trafficking, Fibronectin Architecture, and Glomerular Injury upon Adiponectin Receptor 1 Depletion

Background
Deficiency of adiponectin and its downstream signaling may contribute to the pathogenesis of kidney injury in type 2 diabetes. Adiponectin activates intracellular signaling using adiponectin receptor 1 (AdipoR1) and adiponectin receptor 2, but the role of adiponectin receptor–mediated signaling in glomerular injury in type 2 diabetes remains unknown.

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 body mass index 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 yes-associated protein–mediated mechanoresponse and induced accumulation of the extracellular matrix (ECM) protein fibronectin in the glomeruli in vivo and podocytes in vitro. Functionally, AdipoR1 deficiency impaired endocytosis of the ECM receptor active integrin β1, disturbed focal adhesion turnover, and remodulated podocyte-derived ECM, thereby reducing podocyte adhesion.

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.