Leonurine alleviates ferroptosis in cisplatin‐induced acute kidney injury by activating the Nrf2 signalling pathway

Abstract

Background and purpose: Evidence indicates that ferroptosis plays a key role in acute kidney injury induced by cisplatin. The Nrf2/NRF2 pathway regulates oxidative stress, lipid peroxidation and positively regulates cisplatin-induced acute kidney injury, but its effect along with the alkaloid leonurine, found in motherwort, on ferroptosis after such acute kidney injury remains unclear.Experimental Approach: The anti-ferroptotic effects of Nrf2 and leonurine were assessed in a mouse model of cisplatin-induced acute kidney injury. In vitro, the effects of leonurine on erastin-and RSL3-induced HK-2 human PTEC ferroptosis were examined. Key Results: Nrf2 deletion induced ferroptosis-related protein expression and iron accumulation in vivo, aggravating cisplatin-induced acute kidney injury. Leonurine activated Nrf2 and prevented iron accumulation, lipid peroxidation and ferroptosis in vitro, being abolished in siNrf2-treated cells. Moreover, leonurine potently inhibited cisplatin-induced renal damage, as assessed by of serum creatinine, blood urea nitrogen, kidney injury molecule-1 and NGAL. Importantly, leonurine activated the Nrf2 antioxidative pathway and preventing changes in ferroptosis-related morphological and biochemical indicators, malondialdehyde level, SOD and GSH depletion, and GPX4 and xCT down-regulation, in cisplatin-induced acute kidney injury. Nrf2 KO mice were more susceptible to ferroptosis after cisplatin-induced acute kidney injury than control mice. The protective effects of leonurine on acute kidney injury and ferroptosis were largely abolished in Nrf2 KO mice. Conclusion and Implications: These data suggest that renal protective effects of Nrf2 activation on cisplatin-induced acute kidney injury are achieved, at least partially, by inhibiting lipid peroxide-mediated ferroptosis, highlighting the potential of leonurine in acute kidney injury treatment.

Bibliometric and visual analysis of nephrotoxicity research worldwide

“…The frontiers research studies demonstrated that cisplatin-induced nephrotoxicity could be inhibited by preventing mitochondrial fragmentation and subsequent cell injury and death through sirtuin 3-dependent mitochondrial dynamics remodeling underlying honokiol intervention ( Mao et al, 2022 ). Also, the role of the renoprotective effect of leonurine hydrochloride was achieved by inhibition of lipid peroxide-mediated ferroptosis and activation of Nrf2 ( Hu et al, 2022 ). In addition, renalase agonists may be a new tool to enhance the renoprotective effects ( Curry and McCormick, 2022 ).…”

Scutellarin protects the kidney from ischemia/reperfusion injury by targeting Nrf2

“…9 For example, one of the TCMs, Leonurine hydrochloride, protects the kidney from CI-AKI by Nrf2 activation and inhibiting lipid peroxide. 32 In addition, the protective effect of Nrf2 activation on kidney was also proved in the lipopolysaccharide (LPS)-induced AKI model under Arbutin. 33 Therefore, we conducted molecular docking experiments with Scu and Nrf2.…”

A FRET biosensor, SMART, monitors necroptosis in renal tubular epithelial cells in a cisplatin-induced kidney injury model

“…Of note, the numbers of cells showing the increased FRET/CFP ratios were relatively few, even in the occluded tubules of the cisplatin-treated kidneys of SMART Tg mice. This suggests that another type of cell death, such as apoptosis, ferroptosis, or necrosis, may simultaneously occur in cisplatin-induced kidney injury 39,40 . The mechanisms underlying cisplatin-induced necroptosis are still a matter of debate.…”