Nitrative Stress-Related Autophagic Insufficiency Participates in Hyperhomocysteinemia-Induced Renal Aging

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.

Decreased autophagy of vascular smooth muscle cells was involved in hyperhomocysteinemia‐induced vascular ageing

“…HHcy is closely related to the occurrence and development of age‐related diseases, such as stroke, 21,22 cardiac hypertrophy 23 and atherosclerosis 24 . At the same time, HHcy could induce endothelial cells senescence, 7 renal ageing, 25 and cognitive vascular dysfunction 26 . As we know, vascular aging is one of the bases of cardiovascular diseases 27 .…”

Mechanism of homocysteine-mediated endothelial injury and its consequences for atherosclerosis

“…HHcy occurs in the early stage of chronic renal failure and further increases with the progression of renal failure. Elevated Hcy can further aggravate renal injury by inducing oxidative stress ( 47 ), insufficient autophagy and renal aging ( 48 ), forming a negative feedback loop. Elevated plasma Hcy level in patients with malignant tumors may be related to changes in methionine metabolism in tumor cells ( 49 ).…”

Genetic Evidence Supporting the Causal Role of Homocysteine in Chronic Kidney Disease: A Mendelian Randomization Study

“…The mechanisms linking tHcy to renal function injury may be mediated by insufficient autophagy. In a diet-induced hyper-Hcy rat model, increased serum Hcy could decrease the expression of a critical transcription factor of autophagy-related genes, the transcription factor EB (TFEB), which further inhibits the activation of TFEB-mediated autophagy ( 28 ). In previous studies, it is noted that the endothelial autophagy of kidneys is crucial for protecting glomeruli from oxidative stress and accordingly maintaining the integrity of glomerular capillaries ( 29 ).…”