Hyperhomocysteinemia exacerbates acute kidney injury via increased mitochondrial damage

Abstract

Acute kidney injury (AKI) is a complex and common set of multifactorial clinical syndromes, and associated with increased in-hospital mortality. There is increasing evidence that Hyperhomocysteinemia (HHcy) is highly associated with the development of a variety of kidney diseases, including AKI. However, the pathogenesis of HHcy in AKI remains unclear. In this study, we investigated the effect and mechanism of HHcy on cisplatin-induced AKI in mice and NRK-52E cells cultured with HHcy. We confirmed that mice with HHcy had higher serum levels of creatinine and more severe renal tubule injury after cisplatin injection. We found that HHcy aggravated renal mitochondrial damage, mainly manifested as decreased ATP β, significantly increased cytoplasmic Cyt C expression and the ADP/ATP ratio, and a significantly decreased mitochondrial DNA (mtDNA) copy number. In addition, we found that HHcy accelerated cisplatin-induced renal DNA damage; culturing NRK-52E cells with homocysteine (Hcy) could significantly increase apoptosis and mitochondrial damage. Interestingly, we found that Mdivi-1 reduced Hcy-induced mitochondrial damage, thereby reducing the level of apoptosis. In conclusion, these results suggest that HHcy might aggravate the development of AKI by increasing mitochondrial damage and that reducing Hcy levels or inhibiting mitochondrial damage may be a potential therapeutic strategy to delay the development of AKI.

Folic Acid Protects against Ethanol-Induced Hepatic Mitophagy Imbalance by ROS Scavenging and Attenuating the Elevated Hcy Levels

“…Thus, Hcy-triggered vicious mitochondrial damage and mitophagy were prominently hampered by folic acid administration. In line with prior research, Mdivi-1, an inhibitor of Drp1, also inhibited Hcy elicited mitochondrial division and mitophagy and reduced the initiation of endogenous apoptotic signals by restricting the release of mtDAMPs into the cytosol. , Therefore, Hcy conferred an important mediator of alcohol-elevated mitophagy in the current experiment, and folic acid may restore ethanol-induced mitochondrial dysfunction and impede ethanol-activated mitophagy, at least in part, by facilitating the process of Hcy transmethylation.…”

“…In addition, the elevated serum TBARS and the considerably decreased GSH/GSSG in erythrocytes that occurred along with the lower folic acid concentrations in ALD patients suggest that aberrant Hcy metabolism may play a key role in oxidative stress. , However, in an acute kidney-injured model, Hcy damages the mitochondria and initiates apoptosis by increasing cytochrome C levels in the cytoplasm, reducing ATP synthase activity and mtDNA quantity. In contrast, such detrimental effects caused by Hcy were abrogated by the mitochondrial division inhibitor Mdivi-1 . Therefore, we speculate that folic-acid-mediated mitophagy may be related to its transmethylation in Hcy metabolism.…”

“…In contrast, such detrimental effects caused by Hcy were abrogated by the mitochondrial division inhibitor Mdivi-1. 26 Therefore, we speculate that folic-acid-mediated mitophagy may be related to its transmethylation in Hcy metabolism.…”

“…Elevated Hcy also increases oxidative stress in brain cells, vascular endothelial cells, and hepatocytes; exacerbate the degree of mitochondria-mediated endogenous apoptosis; and trigger mitochondrial remodeling and mitophagy . Thus, Hcy is a pivotal contributor to both mitochondrial dysfunction and dynamic imbalance in previous studies. – In contrast, a combined treatment of folic acid and vitamin B12 could improve alcohol-induced liver injury by normalizing plasma Hcy levels . Analogously, tetrahydrocurcumin, an antioxidant, can counteract the oxidative damage of Hcy, ameliorate the Hcy-induced mitochondrial splitting condition, and prevent the occurrence of mitophagy …”

Timing of Initiation of Kidney Replacement Therapy in Acute Kidney Injury in the Critically Ill Patient

“…Hyperhomocysteinemia has been described in AKI, which aggravates mitochondrial damage and may be a factor in increasing apoptosis of renal tubular epithelial cells and perpetuating the damage [100,107].…”