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.
Highlights
Cisplatin is a commonly used chemotherapeutic drug for solid tumors [1]
We investigated the role of hypoxia inducible factor1α (HIF-1α) in the mitigation of cisplatin-induced nephrotoxicity by Panax notoginseng saponins (PNS) in a rat model
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/ BCL2/ adenovirus E1B 19kDa-interacting protein 3 (BNIP3)/Beclin-1 signaling pathway
Summary
Cisplatin (cis-diamminedichloroplatinum II) is a commonly used chemotherapeutic drug for solid tumors [1]. The renal toxicity of cisplatin limits its clinical application [2]. The precise mechanism of cisplatin-induced nephrotoxicity (CIN) has not been fully understood. Previous studies showed the involvement of oxidative stress [3], inflammation [4] and apoptosis [5] as plausible mechanisms of CIN. Effective therapeutic strategies are not available as yet for CIN. Novel therapeutic agents are needed for treating CIN in patients that need cisplatin-based chemotherapy. Recent studies have shown that autophagy protects against cisplatin-induced acute kidney injury [6]. Mitophagy, which removes damaged mitochondria protects against CIN [7]
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