Leonurine alleviates ferroptosis in cisplatin-induced acute kidney
injury by activating the Nrf2 signaling pathway
Abstract
Background and purpose: Increasing evidence suggests that ferroptosis
plays a key role in the pathophysiology of acute kidney injury induced
by cisplatin. The Nrf2 signaling pathway regulates oxidative stress and
lipid peroxidation and positively regulates cisplatin-induced AKI
(CI-AKI). However, Nrf2 and its activator leonurine on ferroptosis after
CI-AKI remain unclear. Experimental Approach: The anti-ferroptotic
effects of Nrf2 and its activator leonurine were assessed using a mouse
model of cisplatin-induced AKI. In vitro, the potential effects of
leonurine on erastin- and RSL3-induced HK-2 human PTEC ferroptosis were
examined. Key Results: As expected, Nrf2 deletion induced
ferroptosis-related protein expression and iron accumulation in vivo,
further aggravating CI-AKI. The Nrf2 activator leonurine prevented iron
accumulation and lipid peroxidation and inhibited ferroptosis in vitro,
while these effects were abolished in siNrf2-treated cells. Moreover,
leonurine potently ameliorated cisplatin-induced renal damage, as
indicated by the assessment of SCr, BUN, KIM-1, and NGAL. Importantly,
leonurine activated the Nrf2 antioxidative signaling pathway and
prohibited changes in ferroptosis-related morphological and biochemical
indicators, such as the MDA level, SOD and GSH depletion and GPX4 and
xCT downregulation, in CI-AKI. Moreover, Nrf2 KO mice were more
susceptible to ferroptosis after CI-AKI than control mice, and the
protective effects of leonurine on AKI and ferroptosis were largely
abolished in Nrf2 KO mice. Conclusion and Implications: These data
suggest that the renal protective effects of Nrf2 and its activator
leonurine on CI-AKI are achieved at least partially by inhibiting lipid
peroxide-mediated ferroptosis and highlight the potential of leonurine
as a CI-AKI treatment.