Elevated aerobic glycolysis in renal tubular epithelial cells influences the proliferation and differentiation of podocytes and promotes renal interstitial fibrosis.

Abstract

The aim of this study was to elaborate the influence of changing energy metabolism pattern of renal tubular epithelial cells in the process of renal interstitial fibrosis on podocytes. Meanwhile, we also investigated the relationship between energy metabolism pattern and the development of renal interstitial fibrosis. We established a model of renal interstitial fibrosis by unilateral ureteral obstruction (UUO). The protein and messenger RNA (mRNA) expression of fibrosis signs, such as α-smooth muscle actin (α-SMA) and fibronectin (FN) were detected. We also measured the protein and mRNA expression of key glycolytic enzymes, including pyruvate kinase muscle isozyme 2 (PKM2) and human glandular kallikrein 2 (HK2). The proliferation and differentiation of podocytes during fibrosis were observed by monitoring the expression of nephrin and myocardin. In vitro experiments, primary podocytes were extracted, cultured, and stimulated with lactate. Then the alterations during the process were observed. Finally, PKM2 expression was inhibited by intravenous infusion of the plasmid. The link between the expression of marker protein as well as differentiation protein in podocytes and renal interstitial fibrosis was analyzed. During the process of renal interstitial fibrosis, phenotypic changes and enhanced expression of fibrosis and proliferation markers were found in fibroblasts. Meanwhile, in renal tubular epithelial cells, increased expression of key enzymes of glycolysis, the level of glycolysis as well as lactate metabolites cooperatively led to hypoxic and acidic environment, eventually inhibiting the proliferation and differentiation of podocytes and aggravating fibrosis. When the level of glycolysis in renal tubular epithelial cells was reduced, the number and function of podocytes were partially restored, and renal interstitial fibrosis was alleviated. During renal interstitial fibrosis, glycolysis of renal tubular epithelial cell was increased, leading to the recodification of energy metabolism. This process affected the number and function of podocytes and aggravated renal interstitial fibrosis.