Total extract of Abelmoschus manihot L. alleviates uric acid-induced renal tubular epithelial injury via inhibition of caspase-8/caspase-3/NLRP3/GSDME signaling

Abstract

Purpose: The incidence of uric acid (UA)-induced kidney injury is increasing owing to the high incidence of hyperuricemia in recent years. The flower of Abelmoschus manihot (Linneus) Medik is a traditional Chinese medicinal herb widely used in the treatment of some kidney diseases. In our previous study, we reported that the total extract of A. manihot L. flower (TEA) attenuated adriamycin-induced renal tubular cell injury. In this study, we aimed to evaluate the role of TEA in UA-induced tubular cell injury.Methods: Normal rat proximal epithelial NRK-52E cells were incubated with UA to mimic hyperuricemia conditions. The role of TEA in the renal tubular cells was also assessed. The cellular morphology was observed using phase-contrast microscopy, and cell viability was analyzed using the Cell Counting kit-8. Living and dead cells were stained using a Calcein-AM/PI double stain kit. The release of lactate dehydrogenase (LDH) was analyzed by LDH cytotoxicity Assay Kit. The expression of target proteins was analyzed using western blot analysis.Results: UA triggered NRK-52E cell injury, as evidenced by morphological changes, detachment of cells from the bottom, cell swelling, large bubbles blowing from cell membrane and loss of cell viability. UA increased release of LDH. UA induced the expression of p-ERK1/2 and the subsequent activation of caspase-8, caspase-3, and NLRP3 inflammasomes. Pyroptosis was elicited by UA after gasdermin E N-terminal (GSDME-NT) was cleaved from gasdermin E (GSDME). Z-DEVD-FMK, a caspase-3 inhibitor, suppressed the expression of both NLRP3 and GSDME-NT, but not that of caspase-8. INF39, an NLRP3 inhibitor, altered the expression of GSDME-NT expression, but not that caspase-3 and caspase-8. TEA alleviated UA-induced cell injury by suppressing ERK1/2/caspase-8/caspase-3/NLRP3/GSDME signaling.Conclusion: GSDME-mediated pyroptosis was involved in UA-induced renal tubular cell injury. This is the first study to report that TEA protects renal tubular epithelial cells against UA by inhibiting the ERK/1/2/caspase-8/caspase-3/NLRP3/GSDME pathway.

Effect of tea intake on genetic predisposition to gout and uric acid: a Mendelian randomization study

“…Ding Z et al. ( 57 ) reported that tea protects renal tubular epithelial cells by inhibiting the pyroptosis pathway, thereby attenuating the damage caused by uric acid to the kidneys. It has also been reported that tea and its extracts inhibit the growth of glomerular membrane cells, thereby delaying the progression of renal failure ( 58 , 59 ).…”

“…It has also been shown that tea reduces the formation of inflammatory factors induced by urate crystals and inhibits the activation of the NLRP3 inflammatory vesicle and NF-kB pathway (55), thereby decreasing the likelihood of gout in patients (45). Zhang Y et al (56) found that tea increases the eGFR level and reduces the risk of chronic kidney disease and proteinuria. Ding Z et al (57) reported that tea protects renal tubular epithelial cells by inhibiting the pyroptosis pathway, thereby attenuating the damage caused by uric acid to the kidneys.…”

SLC2A9 rs16890979 reduces uric acid absorption by kidney organoids

“…It is considered that a serum UA concentration exceed of 6 mg/dL (360μM, 0.36 mM) is defined as HUA, while a serum UA concentration of 1 mM is relatively rare in the human body ( Pascart and Lioté, 2018 ). The concentrations of UA applied in vitro to mimic hyperuricosuria conditions have usually been set at approximately the 1 mM ( Liu et al, 2022 ; Shi et al, 2023 ) to 3 mM ( Ding et al, 2022 ) levels. In this study, we found pronounced tissue impairment, presenting as increased renal fibrosis and EMT-related molecule upregulation, in organoids exposed to 1 mM UA for 24 h, demonstrating the vulnerability of the organoids to the UA challenge.…”

Pyroptotic cell death: an emerging therapeutic opportunity for radiotherapy

“… [ 84 ] Total extract of Abelmoschus manihot L Inhibition of caspase-8/caspase-3/NLRP3/GSDME signaling. [ 85 ] Dextmedetomidine It inhibits GSDMD by activating the PI3K/AKT/GSK3β pathway. [ 86 ] Esculetin Inhibition of pyroptosis through NF-κB/NLRP3 signaling pathway.…”