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Animal Models

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

International Journal of Obesity (2024)Cite this article

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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.

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Fig. 1: WNIN/Ob rats are presented with normoglycemia but hyperinsulinemia.
Fig. 2: WNIN/Ob rats have impaired kidney function.
Fig. 3: WNIN/Ob rats exhibit glomerulosclerosis.
Fig. 4: Podocyte injury in WNIN/Ob rats.
Fig. 5: WNIN/Ob rats show elevated expression of mesenchymal markers.
Fig. 6: Glomerular injury and proteinuria in high-fat-diet-fed mice are concomitant with induction of WT1.
Fig. 7: Expression of WT1 in high-fat-diet-fed mice.
Fig. 8: Co-expression of mesenchymal markers with WT1 in CKD.
Fig. 9: WT1 promoter analysis revealed SREBFs binding sites.

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Data availability

The data used in this study are available from the corresponding author on reasonable request.

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Acknowledgements

Authors thank Dr. Srinivas Kethavath for the help with gene network analysis and Dr. Raghu Ganugula for assistance with Masson’s trichrome staining. AKP acknowledges DST-FIST and DBT-BUILDER support to the Department of Biochemistry, SLS, UoH.

Funding

This work was supported by funding from the SERB (CRG/2019/005789 to GBR & AKP) and funds from the ICMR (5/9/1447/2022-NUT to GBR and 5/4/7-12/Nephro/2022-NCD-II to AKP). SJ is supported by a Postdoctoral Fellowship from ICMR.

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  1. These authors contributed equally: Sneha Jakhotia, Rajesh Kavvuri.

Authors and Affiliations

  1. Department of Biochemistry, ICMR-National Institute of Nutrition, Hyderabad, 500007, TS, India

    Sneha Jakhotia & G. Bhanuprakash Reddy

  2. Department of Biochemistry, University of Hyderabad, Hyderabad, 500046, TS, India

    Rajesh Kavvuri, Sumathi Raviraj, Somorita Baishya & Anil Kumar Pasupulati

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GBR and AKP conceived the research, designed experiments, reviewed and edited the manuscript; SJ and RK performed the experiments, analyzed the data and wrote the manuscript; SR and SB performed the experiments and analyzed the data.

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Correspondence to Anil Kumar Pasupulati or G. Bhanuprakash Reddy.

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Jakhotia, S., Kavvuri, R., Raviraj, S. et al. Obesity-related glomerulopathy is associated with elevated WT1 expression in podocytes. Int J Obes (2024). https://doi.org/10.1038/s41366-024-01509-3

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