Withaferin A protects against hyperuricemia induced kidney injury and its possible mechanisms

Abstract

The study was designed to explore the effects of Withaferin A (WFA) on hyperuricemia-induced kidney injury and its action mechanism. Potassium oxonate (PO) was employed to establish the hyperuricemic mouse model. The pathological changes of renal tissue were evaluated by hematoxylin-eosin and masson trichrome staining. The levels of creatinine, blood urea nitrogen (BUN), uric acid (UA) and xanthine oxidase (XOD) were detected using corresponding commercial kits. Expressions of collagen-related and apoptosis-associated proteins in renal tissues were, respectively, evaluated by immunofluorescence and western blotting. Cell apoptosis was detected by TUNEL assay, and transporter expressions using western blotting. Followed by WFA, NRK-52E cells were treated with UA before evaluation of apoptosis and fibrosis. Results indicated that WFA ameliorated renal damage, improved kidney function, and decreased levels of creatinine, BUN, UA, and XOD in PO-induced hyperuricemic mice. Furthermore, WFA significantly prevented renal fibrosis and increased the expression of collagen-related proteins. Similarly, WFA markedly inhibited renal apoptosis, accompanied by changes of apoptosis-related proteins. Importantly, expression of transporters responsible for the secretion of organic anion transporter 1 (OAT1), OAT3, ATP-binding cassette subfamily G member 2 (ABCG2) was remarkably enhanced whereas that of urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) was reduced in renal tissues of mice with hyperuricemia. In vitro study revealed that WFA notably ameliorated UA-induced cell fibrosis and apoptosis. Taken together, WFA improves kidney function by decreasing UA via regulation of XOD and transporter genes in renal tubular cells.

Treg/Th17 Ratio Regulation May Play an Important Role in Epigallocatechin-3-Gallate–Mediated Attenuation of Increased Afterload-Induced Cardiac Hypertrophy

“…The paraffin block was cut into 5 µm sections and then subjected to hematoxylin and eosin and Masson's trichome staining. 15 Microscopic inspection was completed by a board-certified pathologist in a blinded manner.…”

Quercetin alleviates chronic renal failure by targeting the PI3k/Akt pathway

“…DAPI incubation was performed in the dark for 5–10 min, following three cycles of washing with PBS, 1 min each cycle. The sections were sealed and placed under a microscope for photographing [ 18 ] .…”

Therapeutic Implications of Ferroptosis in Renal Fibrosis

“…In different models, artemisinin and its derivatives have been reported to induce ferroptosis by triggering ROS, promoting ferritin degradation, and regulating xCT/GPX4 axis ( Louandre et al, 2013 ; Louandre et al, 2015 ; Sun et al, 2016 ), thus alleviating renal fibrosis ( Cao et al, 2016 ; Zhang et al, 2017 ; Wen et al, 2019 ; Zhang et al, 2019 ; Liu et al, 2020 ). Withaferin A can down-regulate pro-fibrotic factors, inflammatory signaling molecules, and ER stress-related molecules and improve kidney function by decreasing uric acid ( Chen et al, 2020 ; Zhao et al, 2021 ), it could also induce ferroptosis via the NRF2 pathway by targeting KEAP1 or inactivating GPX4 ( Hassannia et al, 2018 ).…”