Evaluation of glomerular sirtuin-1 and claudin-1 in the pathophysiology of nondiabetic focal segmental glomerulosclerosis.

Autor: Lopes-Gonçalves G; Laboratory of Renal Physiology, Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, 1524 Prof. Lineu Prestes Avenue, Sao Paulo, 05508-000, Brazil. ggoncalves@usp.br., Costa-Pessoa JM; Laboratory of Renal Physiology, Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, 1524 Prof. Lineu Prestes Avenue, Sao Paulo, 05508-000, Brazil., Pimenta R; Laboratory of Medical Investigation (LIM 55), Urology Department, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil., Tostes AF; Laboratory of Neurobiology, Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil., da Silva EM; Department of Nephrology, Paulista School of Medicine, Federal University of Sao Paulo, Sao Paulo, Brazil., Ledesma FL; Department of Pathology, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil., Malheiros DMAC; Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil., Zatz R; Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil., Thieme K; Laboratory of Cellular and Molecular Bases of Renal Physiology, Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil., Câmara NOS; Department of Nephrology, Paulista School of Medicine, Federal University of Sao Paulo, Sao Paulo, Brazil.; Laboratory of Transplantation Immunobiology, Department of Immunology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil., Oliveira-Souza M; Laboratory of Renal Physiology, Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, 1524 Prof. Lineu Prestes Avenue, Sao Paulo, 05508-000, Brazil. souza@icb.usp.br.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2023 Dec 19; Vol. 13 (1), pp. 22685. Date of Electronic Publication: 2023 Dec 19.
DOI: 10.1038/s41598-023-49861-0
Abstrakt: Focal segmental glomerulosclerosis (FSGS) is the leading cause of nephrotic syndrome, which is characterized by podocyte injury. Given that the pathophysiology of nondiabetic glomerulosclerosis is poorly understood and targeted therapies to prevent glomerular disease are lacking, we decided to investigate the tight junction protein claudin-1 and the histone deacetylase sirtuin-1 (SIRT1), which are known to be involved in podocyte injury. For this purpose, we first examined SIRT1, claudin-1 and podocin expression in kidney biopsies from patients diagnosed with nondiabetic FSGS and found that upregulation of glomerular claudin-1 accompanies a significant reduction in glomerular SIRT1 and podocin levels. From this, we investigated whether a small molecule activator of SIRT1, SRT1720, could delay the onset of FSGS in an animal model of adriamycin (ADR)-induced nephropathy; 14 days of treatment with SRT1720 attenuated glomerulosclerosis progression and albuminuria, prevented transcription factor Wilms tumor 1 (WT1) downregulation and increased glomerular claudin-1 in the ADR + SRT1720 group. Thus, we evaluated the effect of ADR and/or SRT1720 in cultured mouse podocytes. The results showed that ADR [1 µM] triggered an increase in claudin-1 expression after 30 min, and this effect was attenuated by pretreatment of podocytes with SRT1720 [5 µM]. ADR [1 µM] also led to changes in the localization of SIRT1 and claudin-1 in these cells, which could be associated with podocyte injury. Although the use of specific agonists such as SRT1720 presents some benefits in glomerular function, their underlying mechanisms still need to be further explored for therapeutic use. Taken together, our data indicate that SIRT1 and claudin-1 are relevant for the pathophysiology of nondiabetic FSGS.
(© 2023. The Author(s).)
Databáze: MEDLINE
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