Circulating RAC1 contributed to steroid-sensitive nephrotic syndrome: Mendelian randomization, single-cell RNA-sequencing, proteomic, and experimental evidence.

Autor:	Zhang Y; Department of Nephrology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China., Yao T; Department of Nephrology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China., Xu Y; Department of Nephrology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China., Wang Y; Department of Nephrology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China., Han S; Department of Nephrology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Jazyk:	angličtina
Zdroj:	Renal failure [Ren Fail] 2024 Dec; Vol. 46 (2), pp. 2416087. Date of Electronic Publication: 2024 Oct 18.
DOI:	10.1080/0886022X.2024.2416087
Abstrakt:	Objectives: The small GTPase Rac1 (RAC1) has been linked to podocyte disorders and steroid-sensitive nephrotic syndrome (SSNS). The aim of this study was to explore and validate the potential causal association between circulating RAC1 and SSNS. Methods: The association between circulating RAC1 and SSNS at both gene expression and proteomic levels was investigated using Mendelian randomization analysis, and further validated by single-cell RNA-sequencing, proteomic analysis, and experimental studies. The genetic instruments comprised cis-expression quantitative trait loci (cis-eQTLs) associated with RAC1 gene expression and protein QTLs correlated with plasma RAC1 protein levels. Causal associations were estimated utilizing the inverse variance weighted and MR-PRESSO methods. Validation of RAC1 expression was conducted through single-cell RNA-sequencing of peripheral blood mononuclear cells from patients with SSNS and healthy controls. Proteomic analysis was performed among patients with minimal change nephrotic syndrome. Experimental validation was conducted using a puromycin aminonucleoside (PAN)-induced nephrosis model. Results: Increased expression of RAC1 was associated with a higher risk of SSNS (gene expression level: odds ratio [OR], 1.53; 95% confidence interval [CI], 1.02-2.28; protein level: OR, 1.82; 95% CI, 1.05-3.17). The results of MR-PRESSO were consistent (gene expression level: OR, 1.49; 95% CI, 1.17-1.92; protein level: OR, 1.81; 95% CI, 1.16-2.85). Single-cell RNA sequencing and proteomic analysis confirmed elevated RAC1 expression in patients with SSNS compared to healthy controls. Experimental data further supported increased RAC1 expression in PAN-induced nephropathy. Conclusions: Increased expression of RAC1 might be causally associated with SSNS, suggesting that targeting RAC1 might represent a potential therapeutic strategy for SSNS.
Databáze:	MEDLINE
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