Date Published: December 24, 2018
Publisher: Impact Journals
Author(s): Buhui Liu, Yue Tu, Weiming He, Yinglu Liu, Wei Wu, Qijun Fang, Haitao Tang, Renmao Tang, Ziyue Wan, Wei Sun, Yigang Wan.
The kidney is a typical organ undergoing age and injury. Hyperoside is reported to be useful for preventing aging induced by D-galactose (D-gal). However, therapeutic mechanisms remain unclear. We thereby aimed to verify whether hyperoside, compared to vitamin E (VE), could alleviate renal aging and injury by regulating autophagic activity and its related signaling pathways. In vivo, rats were administered with either hyperoside or VE after renal aging modeling induced by D-gal. Changes in renal aging and injury markers, autophagic activity and AMPK-ULK1 signaling pathway in the kidneys were analysed. In vitro, the NRK-52E cells exposed to D-gal were used to investigate regulative actions of hyperoside and VE on cell viability, renal tubular cellular aging markers, autophagic activity and its related signaling pathways by histomorphometry, immunohistochemistry, immunofluorescence, lentiviral transfection and Western blot. Aging and injury in the kidneys and renal tubular cells induced by D-gal were ameliorated by hyperoside and VE. Hyperoside and VE inhibited autophagic activity through mTOR-independent and AMPK-ULK1 signaling pathways. Hyperoside, as a component of phytomedicine similar to VE, attenuated renal aging and injury induced by D-gal via inhibiting AMPK-ULK1-mediated autophagy. This study provides the first evidence that hyperoside contributes to the prevention of age-associated renal injury.
Aging is defined as a decline in performance and fitness with advanced age [1,2]. The aging process is universal for almost all multicellular organisms, in which the kidney is a typical organ that undergoes age and injury characterized respectively by cell cycle arrest in G1 phase (p21/p53 proteins), shortened telomeres, staining for senescence-associated-β-galactosidase (SA-β-gal), inflammaging (the secretion of senescence-associated secretory phenotype, SASP) and renal interstitial fibrosis/tubular atrophy (IF/TA) [3–6]. Despite this, there is currently little in vivo and in vitro information on the therapeutic effects and mechanisms underlying renal age and injury. Xu et al. reported that klotho highly expressed in the kidneys and brain is an anti-aging gene encoding a single-pass transmembrane protein, which serves as an aging suppressor through a wide variety of mechanisms, including anti-oxidation, anti-senescence and modulation of many signaling pathways . Many experiments confirmed that destruction of the klotho protein or loss of the klotho function leads to an accelerated aging. Therefore, the klotho protein may be a promising therapeutic target for renal age and injury . Furthermore, recently, to analyze the pharmacological basis of anti-renal aging, several studies are developed. In these studies, calorie restriction (CR) has been shown to be the most robust nongenetic or pharmacological approach to understanding this phenomenon . It has been reported that short-term CR may be considered a potential intervention for the retardation of renal aging by increasing autophagy and, subsequently, by reducing oxidative damage . In addition, Calvo-Rubio et al. reported that long-term CR partially prevented or delayed the appearance of several structural hallmarks and autophagic processes in the aged kidneys . Accordingly, Kume et al. also found that the reduced autophagy in the kidney might be involved in the age-associated weakness of proximal tubular cells (PTCs) against various renal lesions . Undoubtedly, these results strongly suggest that autophagy, as the current focus of aging, should be helpful in the design of studies aiming to further explore anti-renal aging and should lead to the establishment of novel clinical treatments that may delay the progression of age-associated renal dysfunction in elderly patients.
In the present study, we demonstrated the following: D-gal induced aging and injury in the kidneys and renal tubular cells, which were ameliorated by the treatment of hyperoside and VE in vivo and in vitro; Hyperoside and VE inhibited autophagic activity induced by D-gal through the mTOR-independent and AMPK-ULK1 signaling pathways in vitro; Hyperoside and VE also depressed autophagic activity induced by D-gal through the AMPK-ULK1 signaling in vivo. Thus, hyperoside and VE alleviated renal aging and injury in vivo and in vitro by inhibiting autophagic activity and AMPK-ULK1 signaling.