Musale, V. | Search bioRxiv

bioRxiv2024

A Novel Role of Hyaluronan and its Membrane Receptors, CD44 and RHAMM in Obesity-Related Glomerulopathy

Obesity-related glomerulopathy (ORG) contributes to diabetic nephropathy and kidney cancer, leading to chronic/end-stage kidney disease. To date, treatments for ORG are limited because of incomplete understanding of the disease pathogenesis. Here, we identified a novel role for hyaluronan (HA) and its membrane receptors, CD44 and RHAMM in obesity-associated renal inflammation, fibrosis, tubular injury, and kidney dysfunction. Pharmacological and genetic ablation of HA, CD44 or RHAMM reversed these renal disorders induced by high fat diet feeding in mice in vivo. Increased HA content, and CD44 and RHAMM expression damaged the kidney via activation of TGF-{beta}1/Smad2/3, P38/JNK MAPK and ROCK/ERK pathways. We further established a link between renal insulin resistance and ECM remodelling using human kidney cells in vitro, shedding mechanistic insight into the role of HA, CD44 and RHAMM in the pathogenesis of ORG. Furthermore, in human kidney biopsies gene expression of CD44 and RHAMM was increased in chronic kidney disease and diabetic nephropathy, and their levels were correlated with markers of kidney (dys)function (GFR, serum creatinine, proteinuria). Our findings provide evidence for HA-CD44/RHAMM as a potential therapeutic target in ORG and consequent prevention of chronic kidney disease.

physiology↗

bioRxiv2023

Extracellular Matrix Abnormalities Contribute to Cardiac Insulin Resistance and Associated Dysfunction in Diet-induced Obese Mice

Increased deposition of extracellular matrix (ECM) components such as collagens and hyaluronan contributes to the pathogenesis of obesity-associated insulin resistance in muscle, liver, and adipose tissue. Despite the significance of the heart in cardiovascular and metabolic diseases, maladaptive ECM remodelling in obesity-associated cardiac insulin resistance and cardiac dysfunction has not been studied. Using genetic and pharmacological approaches in mice fed a high fat (HF) diet, we demonstrated a tight association between increased ECM deposition with cardiac insulin resistance. Increased collagen deposition by genetic deletion of matrix metalloproteinase 9 (MMP9) exacerbated cardiac insulin resistance and decreased hyaluronan deposition by treatment with PEGylated human recombinant hyaluronidase PH20 (PEGPH20) improved cardiac insulin resistance in obese mice. These relationships corresponded to functional changes in the heart. PEGPH20 treatment in obese mice ameliorated HF diet-induced abnormal myocardial remodelling. In addition to hyaluronan, increased collagen deposition is a characteristic of the obese mouse heart. We further demonstrated that pirfenidone, a clinically available anti-fibrotic medication which inhibits collagen expression, improved cardiac insulin resistance and cardiac function in obese mice. Our results provide important new insights into the role of ECM remodelling in the pathogenesis of cardiac insulin resistance and associated dysfunction in obesity of distinct mouse models. These findings support the novel therapeutic potential of targeting early cardiac ECM abnormalities in the prevention and treatment of obesity-related cardiovascular complications.

physiology↗