Inhibition of PFKP in renal tubular epithelial cell restrains TGF-β induced glycolysis and renal fibrosis

Metabolic reprogramming to glycolysis is closely associated with the development of chronic kidney disease (CKD). Although it has been reported that phosphofructokinase 1 (PFK) is a rate-limiting enzyme in glycolysis, the role of the platelet isoform of PFK (PFKP) in kidney fibrosis initiation and progression is as yet poorly understood. Here, we investigated whether PFKP could mediate the progression of kidney interstitial fibrosis by regulating glycolysis in proximal tubular epithelial cells (PTECs). We induced PFKP overexpression or knockdown in renal tubules via an adeno-associated virus (AAV) vector in the kidneys of mice following unilateral ureteral occlusion. Our results show that the dilated tubules, the area of interstitial fibrosis, and renal glycolysis were promoted by proximal tubule-specific overexpression of PFKP, and repressed by knockdown of PFKP. Furthermore, knockdown of PFKP expression restrained, while PFKP overexpression promoted TGF-beta 1-induced glycolysis in the human PTECs line. Mechanistically, Chip-qPCR revealed that TGF-beta 1 recruited the small mothers against decapentaplegic (SMAD) family member 3-SP1 complex to the PFKP promoter to enhance its expression. Treatment of mice with isorhamnetin notably ameliorated PTEC-elevated glycolysis and kidney fibrosis. Hence, our results suggest that PFKP mediates the progression of kidney interstitial fibrosis by regulating glycolysis in PTECs.

Automated summary

Phosphofructokinase 1 (PFK) and its platelet isoform (PFKP) play a significant role in the progression of kidney interstitial fibrosis by regulating glycolysis in proximal tubular epithelial cells (PTECs). Overexpression of PFKP promotes fibrosis and glycolysis, while knockdown of PFKP inhibits these processes. TGF-beta 1 recruits the SMAD3-SP1 complex to enhance PFKP expression, and treatment with isorhamnetin improves glycolysis and kidney fibrosis.