Functional genomics reveals adipose-kidney crosstalk as a contributor to kidney fibrosis via the OSM-OSMR pathway.

Kidney injury is a severe complication of type 2 diabetes, yet its pathophysiology varies among patients. Although abnormal adipose has been identified as an indicator for the risk of kidney injury in type 2 diabetes, the underlying mechanisms remain unclear. Here, we integrated adipose functional genomics and genome-wide association studies of diabetic nephropathy (DN) to investigate the relationship between adipose and kidney injury. By generating the epigenome, transcriptome and regulatome, we constructed functional genomics map of adipose, revealing the regulatory role of perirenal adipose tissue in kidney disease. Integration of the functional genomics with genetic risk demonstrated that the genetic risk of DN is mediated not only through the kidney itself but also via adipose-kidney crosstalk. Our results revealed that risk variant rs2412980 functions through an adipose-specific regulatory element to control the expression of OSM, encoding the cytokine oncostatin-M. Adipose-derived OSM can reprogram OSMR-expressing renal fibroblasts, and subsequent activation of OSM-OSMR pathway is associated with advanced kidney injury, including reduced eGFR, elevated proteinuria and creatinine levels. Our work confirmed the linkage between adipose and kidney diseases with the genetic evidence, and revealed that the adipo-renal axis promotes the fibrosis of kidney under diabetes through the OSM-OSMR pathway.