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

Year: 2025
Type: article
Abstract: 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.
Source: Biomolecules
DOI: 10.3390/biom15111598
Authors: Bingxue Qi, Vishal Musale, Xiong Weng, Ayman K. Banah, Alexander Lawlor, Colin E. Murdoch, Abigail C. Lay, Kate J. Heesom, Richard J. M. Coward, Christopher L. O’Connor, Wenjun Ju, Markus Bitzer, Claire E. Hills, Yang Chen, Li Kang
Institutions: University of Dundee, People 's Hospital of Jilin Province, University of Manchester, University of Bristol, University of Michigan, Michigan Medicine, University of Lincoln, Changchun University of Chinese Medicine
Language: English
Subfield: Cell Biology
Open Access status: gold
Estimated APC paid: $3,258
Funders: Natural Science Foundation of Jilin Province, European Federation of Pharmaceutical Industries and Associations, Halozyme, British Heart Foundation, Diabetes UK, European Commission, China Scholarship Council, Medical Research Council
Awards: Targeting early extracellular matrix abnormalities to treat cardiac insulin resistance and associated dysfunction, Targeting the hyaluronan-CD44/RHAMM pathway in obesity-related kidney damage, G5209516035, G5478580826, Accelerator Award, Extracellular and endothelial regulation of muscle glucose uptake in insulin resistance in vivo, G7449914330, Insulin signalling to the podocyte; pathological importance and therapeutic potential.
OpenAlex ID: W4416198975
FWCI: 0.863
Cites: 61
Cited by: 2
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