A Novel Role of Hyaluronan and Its Membrane Receptors, CD44 and RHAMM, in Obesity-Related Kidney Pathology

Obesity-related kidney pathology (ORKP) is a major global issue that contributes to diabetic nephropathy and kidney cancer and leads to chronic/end-stage kidney disease. Current treatments for ORKP are limited because of the incomplete understanding of the disease pathogenesis. Here, we identified a novel role for hyaluronan (HA) and its membrane receptors, CD44 and RHAMM, in this condition. Obesity-induced increases in HA deposition and CD44 and RHAMM expression are detrimental to the kidney via activation of the TGF-β1/Smad2/3, P38/JNK MAPK, and ROCK/ERK pathways, leading to glomerulopathy, tubular injury, inflammation, albuminuria, and elevated serum creatinine concentrations. Either pharmacological or genetic ablation of HA, CD44, or RHAMM reverses these obesity-driven pathologies in vivo. We further established a mechanistic link between renal insulin resistance and ECM remodelling using human kidney cells in vitro, providing insight into the cell type-specific role of HA, CD44, and RHAMM in the pathogenesis of ORKP. Finally, analysis of glomerular and tubular fractions of human kidney biopsy samples revealed increased expression of CD44 and RHAMM in chronic kidney disease and diabetic nephropathy, and their expression correlated with markers of kidney dysfunction. Our findings provide evidence for HA-CD44/RHAMM as a potential therapeutic target in ORKP and subsequent prevention of chronic kidney disease. While previous studies have implicated CD44 and RHAMM in renal disease and fibrosis, our work for the first time provides an integrated analysis of both receptors in the context of ORKP.