Abstract
High serum levels of free fatty acids (FFAs) could contribute to obesity-induced nephropathy. CD36, a class B scavenger receptor, is a major receptor mediating FFA uptake in renal proximal tubular cells. Empagliflozin, a new anti-diabetic agent, is a specific inhibitor of sodium-glucose co-transporter 2 channels presented on renal proximal tubular cells and inhibits glucose reabsorption. In addition, empagliflozin has shown renoprotective effects. However, the mechanism through which empagliflozin regulates CD36 expression and attenuates FFA-induced lipotoxicity remains unclear. Herein, we aimed to elucidate the crosstalk between empagliflozin and CD36 in FFA-induced renal injury. C57BL/6 mice fed a high-fat diet (HFD) and palmitic acid-treated HK-2 renal tubular cells were used for in vivo and in vitro assessments. Empagliflozin attenuated HFD-induced body weight gain, insulin resistance, and inflammation in mice. In HFD-fed mice, CD36 was upregulated in the tubular area of the kidney, whereas empagliflozin attenuated CD36 expression. Furthermore, empagliflozin downregulated the expression of peroxisome proliferator-activated receptor (PPAR)-γ. Treatment with a PPARγ inhibitor (GW9662) did not further decrease PPARγ expression, whereas a PPARγ antagonist reversed this effect; this suggested that empagliflozin may, at least partly, decrease CD36 by modulating PPARγ. In conclusion, empagliflozin can ameliorate FFA-induced renal tubular injury via the PPARγ/CD36 pathway.
Highlights
Obesity is associated with several pathological conditions, including dyslipidemia, insulin resistance, diabetes mellitus (DM), and low-grade systemic inflammation [1]
We examined the metabolic effects of empagliflozin treatment on high-fat diet (HFD) mice; intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test (IPITT) were performed
These findings suggested that empagliflozin could ameliorate HFD-induced insulin resistance
Summary
Obesity is associated with several pathological conditions, including dyslipidemia, insulin resistance, diabetes mellitus (DM), and low-grade systemic inflammation [1]. CD36, originally known as an FFA transporter, reportedly plays a role in fatty acid oxidation [9] and is expressed in numerous organs and tissues. CD36 is expressed in various cell types within the kidney, including proximal tubular epithelial cells, podocytes, and mesangial cells [6]. In proximal tubular cells, advanced oxidation protein products, such as albumin and palmitate, increase CD36 expression [10]. In a human study, the expression of renal CD36 was reportedly increased in the kidney tissue of patients with DM [5]. CD36 has been shown to contribute to the progression of human diabetic nephropathy via palmitate-induced proximal tubular apoptosis and interstitial fibrosis [15]. Mice with hepatocyte-specific deletion of CD36 attenuates fatty liver and improved insulin sensitivity in HFD-fed mice [17]
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