Obesity-related glomerulopathy is associated with elevated WT1 expression in podocytes

Sneha Jakhotia; Rajesh Kavvuri; Sumathi Raviraj; Somorita Baishya; Anil Kumar Pasupulati; G Bhanuprakash Reddy

doi:10.1038/s41366-024-01509-3

Obesity-related glomerulopathy is associated with elevated WT1 expression in podocytes

Int J Obes (Lond). 2024 Mar 19. doi: 10.1038/s41366-024-01509-3. Online ahead of print.

Authors

Sneha Jakhotia^#¹, Rajesh Kavvuri^#², Sumathi Raviraj², Somorita Baishya², Anil Kumar Pasupulati³, G Bhanuprakash Reddy⁴

Affiliations

¹ Department of Biochemistry, ICMR-National Institute of Nutrition, Hyderabad, 500007, TS, India.
² Department of Biochemistry, University of Hyderabad, Hyderabad, 500046, TS, India.
³ Department of Biochemistry, University of Hyderabad, Hyderabad, 500046, TS, India. anilkumar@uohyd.ac.in.
⁴ Department of Biochemistry, ICMR-National Institute of Nutrition, Hyderabad, 500007, TS, India. reddyg.bp@icmr.gov.in.

^# Contributed equally.

PMID: 38504059
DOI: 10.1038/s41366-024-01509-3

Abstract

Background: The prevalence of obesity is increasing worldwide at an alarming rate. In addition to the increased incidence of cardiovascular and metabolic diseases, obesity is the most potent risk factor for developing chronic kidney disease (CKD). Although systemic events such as hemodynamic factors, metabolic effects, and lipotoxicity were implicated in the pathophysiology of obesity-related glomerulopathy (ORG) and kidney dysfunction, the precise mechanisms underlying the association between obesity and CKD remain unexplored.

Methods: In this study, we employed spontaneous WNIN/Ob rats to investigate the molecular events that promote ORG. Further, we fed a high-fat diet to mice and analyzed the incidence of ORG. Kidney functional parameters, micro-anatomical manifestations, and podocyte morphology were investigated in both experimental animal models. Gene expression analysis in the rodents was compared with human subjects by data mining using Nephroseq and Kidney Precision Medicine Project database.

Results: WNIN/Ob rats were presented with proteinuria and several glomerular deformities, such as adaptive glomerulosclerosis, decreased expression of podocyte-specific markers, and effacement of podocyte foot process. Similarly, high-fat-fed mice also showed glomerular injury and proteinuria. Both experimental animal models showed increased expression of podocyte-specific transcription factor WT1. The altered expression of putative targets of WT1 such as E-cadherin, podocin (reduced), and α-SMA (increased) suggests elevated expression of WT1 in podocytes elicits mesenchymal phenotype. Curated data from CKD patients revealed increased expression of WT1 in the podocytes and its precursors, parietal epithelial cells.

Conclusion: WT1 is crucial during nephron development and has minimal expression in adult podocytes. Our study discovered elevated expression of WT1 in podocytes in obesity settings. Our analysis suggests a novel function for WT1 in the pathogenesis of ORG; however, the precise mechanism of WT1 induction and its involvement in podocyte pathobiology needs further investigation.