Abstract
The kidneys are important organs that are susceptible to aging. Hyperhomocysteinemia (HHcy) is a risk factor for nephropathy and is associated with chronic nephritis, purpuric nephritis, and nephrotic syndrome. Numerous studies have shown that elevated serum homocysteine levels can damage the kidneys; however, the underlying mechanism of HHcy on kidney damage remains unclear. In this study, we make use of a diet-induced HHcy rat model and in vitro cell culture to explore the role of autophagy in HHcy-induced renal aging and further explored the underlying mechanism. We demonstrated that HHcy led to the development of renal aging. Promoted kidney aging and autophagic insufficiency were involved in HHcy-induced renal aging. HHcy decreased the expression of transcription factor EB (TFEB), the key transcription factor of autophagy-related genes in renal tissue. Further experiments showed that nitrative stress levels were increased in the kidney of HHcy rats. Interestingly, pretreatment with the peroxynitrite (ONOO−) scavenger FeTMPyP not only reduced the Hcy-induced nitrative stress in vitro but also partially attenuated the decrease in TFEB in both protein and mRNA levels. Moreover, our results indicated that HHcy reduced TFEB expression and inhibited TFEB-mediated autophagy activation by elevating nitrative stress. In conclusion, this study showed an important role of autophagic insufficiency in HHcy-induced renal aging, in which downregulation of TFEB plays a major role. Furthermore, downexpression of TFEB was associated with increased nitrative stress in HHcy. This study provides a novel insight into the mechanism and therapeutic strategy for renal aging.
Highlights
The incidence of kidney diseases gradually increases in the elderly
We aimed to explore the role of HHcy in renal aging and demonstrate a specific regulatory mechanism of autophagy abnormality induced by HHcy
To investigate the relationship between HHcy and renal aging, we analyzed the expression of aging-related proteins and renal function indicators, which reflected the overall aging of the kidneys
Summary
A thorough understanding of the mechanisms involved in kidney aging is of great significance for the prevention of kidney disease. Hyperhomocysteinemia (HHcy) is associated with kidney damage [1]. Studies have shown that there are various degrees of Hcy metabolic abnormalities in various kidney diseases [2, 3], such as nephrotic syndrome [4], lupus nephritis [5], and chronic nephritis [3, 6, 7], most of which are accompanied by HHcy. On the other hand, HHcy shows an influence on the kidney, causing changes in kidney structure and function and exacerbating kidney damage. Scholars have reached a common consensus that HHcy is an important independent risk factor for kidney disease. Whether or not HHcy can directly induce the progress of renal aging still remains unknown
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