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

Abstract

Glomerular expression of adiponectin receptor 1 (AdipoR1) was lower in people with type 2 diabetes and correlates with podocyte loss. AdipoR1 knockout induced glomerular injury and fibrosis in mice, predominantly in males. AdipoR1 knockdown podocytes showed impaired trafficking of active integrin <i>β</i>1, fibronectin accumulation, impaired adhesion, and increased apoptosis. 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. 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. 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 <i>in vivo</i> and podocytes <i>in vitro</i>. Functionally, AdipoR1 deficiency impaired endocytosis of the ECM receptor active integrin <i>β</i>1, disturbed focal adhesion turnover, and remodulated podocyte-derived ECM, thereby reducing podocyte adhesion. AdipoR1 deficiency in mice resulted in the development of kidney injury predominantly in males. Mechanistically, AdipoR1 loss in podocytes impaired endocytosis of active integrin <i>β</i>1, which plausibly compromised focal adhesion dynamics, disturbed fibronectin matrix turnover, and hindered podocyte adhesion.