Oncostatin M mediates the causal relationship between obesity and chronic kidney disease: evidence from Mendelian randomization and experimental validation

Obesity is a risk factor for chronic kidney disease (CKD). One of the main features of obesity-related glomerulopathy (ORG) is the chronic low-grade inflammatory state. Herein, we aimed to explore the inflammatory proteins that potentially serve as mediators between obesity and CKD by Mendelian randomization (MR) analysis, and to validate the findings by clinical research and animal experiments. Two-step MR and mediation analyses were performed to assess the causal relationships between obesity-related traits and circulating inflammatory proteins and CKD. After identifying Oncostatin M (OSM) as the potential mediator, serum OSM levels of human participants with normal weight, overweight or obesity were assessed. Expression of OSM receptor (OSMR) in the human kidney was validated using publicly available scRNA-seq data. The protein expression and activation of OSMR in the kidneys of obese mice fed a high-fat diet (HFD) were validated by Western blotting. Circulating OSM level is a potential mediator between body mass index (BMI) and CKD, with a mediated proportion of 4.48%. In the clinical study, serum OSM levels were elevated in obese individuals and associated with both BMI and proteinuria. The scRNA-seq analysis found elevated OSMR expression in obese kidneys, with the highest expression level in endothelial cells. The in vivo experiment showed increased protein expression of OSMR, JAK1, and phospho-JAK1 in the kidney of obese mice, indicating activation of OSM/OSMR signaling. We identified circulating OSM levels as a potential mediator in the causal link between obesity and CKD. OSM/OSMR may be a promising target for developing therapeutic strategies for ORG.