Panax notoginseng saponins mitigate cisplatin induced nephrotoxicity by inducing mitophagy via HIF-1α

Abstract

We investigated the role of HIF-1α in the mitigation of cisplatin-induced nephrotoxicity by Panax notoginseng saponins (PNS) in a rat model. Serum creatinine (Scr), blood urea nitrogen (BUN) and urinary N-acetyl-β-D-glucosaminidase (NAG) levels were all elevated in cisplatin treated rats. PNS reduced Scr, BUN and NAG levels in the presence or absence of the HIF-1α inhibitor 2-methoxyestradiol (2ME2). PNS also reduced the high tubular injury scores, which corresponded to renal tubular damage in cisplatin-treated rats and which were exacerbated by 2ME2. Renal tissues from PNS-treated rats showed increased HIF-1α mRNA and nuclear localized HIF-1α protein. Moreover, PNS treatment increased BNIP3 mRNA as well as LC3-II, BNIP3 and Beclin-1 proteins and the LC3-II/LC3-I ratio in rat renal tissues. This suggested that PNS treatment enhanced HIF-1α, which in turn increased autophagy. This was confirmed in transmission electron micrographs of renal tissues that showed autophagosomes in PNS-treated renal tissues. These findings demonstrate that PNS mitigates cisplatin-induced nephrotoxicity by enhancing mitophagy via a HIF-1α/BNIP3/Beclin-1 signaling pathway.

Tilapia Skin Peptides Ameliorate Diabetic Nephropathy in STZ-Induced Diabetic Rats and HG-Induced GMCs by Improving Mitochondrial Dysfunction

“…In the nonalcoholic fatty liver model, the Bnip3 signaling played a key role in alleviating mitochondrial injury and promoting mitophagy [ 49 ]. Panax notoginseng saponins mitigated cisplatin-induced nephrotoxicity by enhancing mitophagy via a hypoxia-inducible factor-1α/Bnip3/Beclin-1 signaling [ 50 ]. The restoration of Nix-mediated mitophagy might be a novel therapeutic target for alleviating proteinuria-induced kidney injury [ 51 ].…”

Molecular Interactions Between Reactive Oxygen Species and Autophagy in Kidney Disease

“…In cisplatin nephrotoxicity, Pink1 or Park2 deficiency caused more apoptosis, mitochondrial dysfunction, and tissue damage both in vitro and in vivo [185,186]. However, a recent study showed that mitophagy induced by Panax notoginseng saponins (PNS) ameliorated cisplatin-induced nephrotoxicity via a HIF-1α/BNIP3/beclin-1 signaling pathway [187]. In contrast-induced AKI, Pink1/Parkin-mediated mitophagy was also induced in renal tubular epithelial cells in vitro [188] and in vivo [188,189,190] models.…”

Mitophagy in Acute Kidney Injury and Kidney Repair

“…Our recent study confirmed the activation of PINK1-and PARK2-dependent mitophagy in renal tubules during cisplatin nephrotoxicity. Using Pink1 or Park2 deficient mice, we provided evidence that PINK1 and PARK2-dependent mitophagy was protective against kidney injury during cisplatin nephrotoxicity [114]. In contrast, a recent study by Zhou et al showed that PINK1 deficiency ameliorated cisplatin-induced mitochondrial fragmentation, mitophagy, and kidney injury in rats [115].…”