Flot2 acts as a novel mediator of podocyte injury in proteinuric kidney disease

Yu, Chunping; Zhang, Hong; Liu, Shuangxin; Li, Ruizhao; Zhao, Xingchen; Chen, Yuanhan; Li, Zhuo; Ma, Jianchao; Wang, Wenjian; Ye, Zhiming; Liang, Xinling; Zhang, Li; Shi, Wei

doi:10.7150/ijbs.78945

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Int J Biol Sci 2023; 19(2):502-520. doi:10.7150/ijbs.78945 This issue Cite

Research Paper

Flot2 acts as a novel mediator of podocyte injury in proteinuric kidney disease

Chunping Yu^1,2*, Hong Zhang^1*, Shuangxin Liu¹, Ruizhao Li¹, Xingchen Zhao¹, Yuanhan Chen¹, Zhuo Li¹, Jianchao Ma¹, Wenjian Wang¹, Zhiming Ye¹, Xinling Liang^1✉, Li Zhang^1✉, Wei Shi^1,3✉

1. Department of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan No. 2 Road, Guangzhou, 510080, China.
2. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
3. Department of Nephrology, Gaozhou People's Hospital, Gaozhou, P. R. China.
*These authors contributed equally to this study.

Citation:

Yu C, Zhang H, Liu S, Li R, Zhao X, Chen Y, Li Z, Ma J, Wang W, Ye Z, Liang X, Zhang L, Shi W. Flot2 acts as a novel mediator of podocyte injury in proteinuric kidney disease. Int J Biol Sci 2023; 19(2):502-520. doi:10.7150/ijbs.78945. https://www.ijbs.com/v19p0502.htm

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Abstract

Podocyte injury is a common hallmark of chronic kidney disease (CKD). The podocin-nephrin complex localized in lipid rafts of podocyte is vital to reduce podocyte injury and proteinuria, however, the mechanism underlying its localization remains unclear. This study uncovers an important role of Flot2 in stabilizing the podocin-nephrin complex localized in lipid rafts. We first confirmed that Flot2 was expressed in podocyte and demenstrated that podocyte-specific Flot2 deletion worsen albuminuria, podocyte injury and glomerular pathology in LPS/ADR-induced nephropathy mouse models. Meanwhile, podocyte injury, albuminuria and pathologic aberrance were prevented in podocyte-specific Flot2 overexpression transgenic mice when challenged with LPS or ADR. Further found that Flot2 was vital to recruit podocin and nephrin into rafts and ameliorated podocyte injury. Flot2 and podocin directly interacted with each other via their SPFH domain. Meanwhile, we also showed that Flot-2 is a direct target of Krüppel-like factor (KLF15). Importanly, we observed that Flot2 was downregulated in renal biopsies from patients with podocytopathies and its expression negatively correlated with proteinuria and positively correlated with eGFR, indicating that Flot2 may be a novel therapeutic target for proteinuric kidney disease.

Keywords: Lipid raft, flot2, podocyte, slit diaphragm protein, proteinuria, chronic kidney disease

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APA

Yu, C., Zhang, H., Liu, S., Li, R., Zhao, X., Chen, Y., Li, Z., Ma, J., Wang, W., Ye, Z., Liang, X., Zhang, L., Shi, W. (2023). Flot2 acts as a novel mediator of podocyte injury in proteinuric kidney disease. International Journal of Biological Sciences, 19(2), 502-520. https://doi.org/10.7150/ijbs.78945.

ACS

Yu, C.; Zhang, H.; Liu, S.; Li, R.; Zhao, X.; Chen, Y.; Li, Z.; Ma, J.; Wang, W.; Ye, Z.; Liang, X.; Zhang, L.; Shi, W. Flot2 acts as a novel mediator of podocyte injury in proteinuric kidney disease. Int. J. Biol. Sci. 2023, 19 (2), 502-520. DOI: 10.7150/ijbs.78945.

NLM

CSE

Yu C, Zhang H, Liu S, Li R, Zhao X, Chen Y, Li Z, Ma J, Wang W, Ye Z, Liang X, Zhang L, Shi W. 2023. Flot2 acts as a novel mediator of podocyte injury in proteinuric kidney disease. Int J Biol Sci. 19(2):502-520.

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