Sodium acetate ameliorates cisplatin-induced kidney injury in vitro and in vivo

Cisplatin (cis-diamminedichloroplatinum(II), CDDP) is the first-line chemotherapeutic agent that is extensively used for the treatment of various tumors but with several serious toxicities both in tumor and normal cells [1]. The adverse side effects of cisplatin treatment include gastrointestinal toxicity, ototoxicity, anorexia and nephrotoxicity among which approximately 20–30% of patients develop nephrotoxicity leading to acute kidney injury (AKI) [[2], [3], [4], [5], [6]]. The intracellular mechanism of cisplatin-induced kidney injury involves, namely, DNA damage, oxidative stress, cytoplasmic organelle dysfunction, inflammation, and apoptosis.

The presence of risk factors, such as age, race, genes, high blood pressure, diabetes, or metabolic syndrome, may cause persistent kidney pressure or maladaptive kidney repair and eventually develop AKI into chronic kidney disease (CKD), which may eventually cause cardiovascular disease, end-stage renal disease, or even death [7]. The normal kidney cells undergo apoptosis or cell necrosis when damaged. Cells could be repaired by cell proliferation under normal circumstances, but cell cycle arrest in the G2/M phase may occur if a cell sustains serious damage. When cells do not undergo apoptosis but induce the expression of the pro-fibrotic factors, TGF-β and CTGF, which cause the cells to move toward fibrosis and eventually develop into end-stage renal disease [8]. Maladaptive repair after AKI has many phenomena similar to kidney ageing [9], which are also found in CKD [10]. Therefore, if AKI develops into CKD, the mechanism may be related to aging.

Short-chain fatty acids (SCFAs) are organic straight-chain saturated fatty acids that are composed of less than six carbons. The most abundant SCFAs in the intestinal tract are acetic acid, propionic acid, and butyric acid. SCFAs are the final product obtained by anaerobic bacteria in the intestines after the fermentation of dietary fiber. This type of fiber cannot be digested and absorbed by humans and is not used until it reaches the colon and rectum. SCFAs have different abundances because of the varying composition of intestinal flora absorbed into the blood circulation by intestinal epithelial cells. SCFAs and bicarbonate HCO3− diffuse from the cell membrane through proton exchange through a pH gradient; SCFAs can also pass through monocarboxylate transport 1 or sodium-coupled monocarboxylate transport 1 in the intestine to dissociate and transport into the circulatory system [11].

Studies on the ameliorating effect of SCFAs on cisplatin-induced kidney damage are few. Most researches on the role of SCFAs in improving kidney disease are based on obesity and diabetic nephropathy. SCFAs promote the tight junction of kidney endothelial cells and maintain the structure of the kidney. After entering the blood circulation, SCFAs inhibit oxidative stress by promoting the performance of superoxide dismutase (SOD) and catalase and reducing the performance of nitric oxide and ROS to reduce glutathione [12]. Mice undergo AKI by cisplatin treatment, which promotes ROS generation [13]. Thus, SCFAs can improve kidney injury by reducing oxidative stress, inflammation, and apoptosis and promoting autophagy; in addition, SCFAs can also improve cell hypoxia by promoting mitochondrial synthesis [14].

Acetic acid is a low-lipophilic, weak organic acid which is the most abundant SCFA in the colon and blood circulation and accounts for about 60% of SCFAs in the intestine. Sodium acetate is a crystalline powder at room temperature and is usually used as an agent in quality improvement, brewing, or food manufacturing. Sodium acetate is easily dissociated into acetate and sodium ions in water, enters cells through diffusion, and is metabolized into acetyl coenzyme A and participates in various physiological metabolisms to generate ATP [15]. Studies have indicated that sodium acetate has a positive effect on the regulation of hepatic lipotoxicity and metabolic syndrome caused by diabetes mellitus in animals [16]. Sodium acetate can promote the expression of glutathione and reduce the production of intracellular ROS induced by lipopolysaccharide [17]; In addition, sodium acetate can improve the insulin resistance of diabetic animals [18].

The damage of cisplatin to the kidney is comprehensive, especially to renal tubular cells. Previous studies showed that cisplatin induced premature renal senescence and renal tubular apoptosis in NRK-52E cells [13,19], and renal fibrosis in rat kidney fibroblast cell line [20]. Recently, mouse glomerular mesangial cells (SV40 MES 13), rat renal proximal tubular cells (NRK-52E) and rat kidney interstitial fibroblasts cells (NRK-49F) have been extensively used in the cisplatin-induced acute kidney injury cell models [[20], [21], [22]]. Therefore, this study will use SV40 MES-13, NRK-52E and NRK-49F cells as cell models to investigate the protective effect of sodium acetate on cisplatin-induced kidney injury.

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