Icariin alleviates renal inflammation and tubulointerstitial fibrosis
via Nrf2-mediated attenuation of mitochondrial damage
Abstract
Tubulointerstitial fibrosis is an inevitable consequence of all
progressive chronic kidney disease (CKD) and contributes to a
substantial health burden worldwide. Icariin, an active flavonoid
glycoside obtained from Epimedium species, exerts potential
antifibrotic effect. The study aimed to explore the protective effects
of icariin against tubulointerstitial fibrosis in unilateral ureteral
obstruction (UUO)-induced CKD mice and TGF-β1-treated HK-2 cells, and
furthermore, to elucidate the underlying mechanisms. The results
demonstrated that icariin significantly improved renal function,
alleviated tubular injuries, and reduced fibrotic lesions in UUO mice.
Furthermore, icariin suppressed renal inflammation, reduced oxidative
stress as evidenced by elevated SOD activity and decreased MDA level.
Additionally, TOMM20 immunofluorescence staining and transmission
electron microscope revealed that mitochondrial mass and morphology of
tubular epithelial cells in UUO mice was improved by icariin. In HK-2
cells treated with TGF-β1, icariin markedly decreased profibrotic
proteins expression, inhibited inflammatory factors, and protected
mitochondria along with improving mitochondrial morphology, reducing
reactive oxygen species (ROS) and mitochondrial ROS (mtROS)
overproduction, and preserving membrane potential. Further
investigations demonstrated that icariin could activate Nrf2/HO-1
pathway both in vivo and in vitro, whereas inhibition of
Nrf2 by ML385 counteracted the protective effects of icariin on
TGF-β1-induced HK-2 cells. In conclusion, icariin protects against renal
inflammation and tubulointerstitial fibrosis at least partly through
Nrf2-mediated attenuation of mitochondrial dysfunction, which suggests
that icariin could be developed as a promising therapeutic candidate for
the treatment of CKD.