Regeneration of glomerular metabolism and function by podocyte pyruvate kinase M2 in diabetic nephropathy

Abstract

Diabetic nephropathy (DN) arises from systemic and local changes in glucose metabolism and hemodynamics. We have reported that many glycolytic and mitochondrial enzymes, such as pyruvate kinase M2 (PKM2), were elevated in renal glomeruli of DN-protected type 1 and type 2 diabetic patients. Here, mice with PKM2-specific overexpression in podocytes (PPKM2Tg) were generated to uncover its renal protective function as potential therapeutic target, which prevented elevated albumin-creatinine ratio (ACR), mesangial expansion, basement membrane thickness and podocyte foot process effacement after 7-months of STZ-induced diabetes. Further, diabetes-induced impairment of glycolytic rate and mitochondrial function were normalized in diabetic PPKM2Tg glomeruli, in concordance with elevated Ppargc1a and Vegf expressions. Restored VEGF expression improved glomerular maximal mitochondrial function in diabetic PPKM2Tg and WT mice. Elevated VEGF levels were observed in the glomeruli of DN-protected patients with chronic type 1 diabetes, and clinically correlated with estimated GFR, but not glycemic control.Mechanistically, the preservations of mitochondrial function and VEGF expression were dependent on tetrameric structure and enzymatic activities of PKM2 in podocyte. These findings demonstrated that PKM2 structure and enzymatic activation in podocytes can preserve entire glomerular mitochondrial function against toxicity of hyperglycemia via paracrine factors such as VEGF and prevent DN progression.

Crosstalk among m6A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application

“…Several studies have demonstrated that m 6 A modulators (e.g., METTL3 and WTAP) affect tumor glucose metabolism by regulating glycolytic enzymes (Warburg effect) to promote proliferation [ 58 – 60 ]. The glycolytic pyruvate kinase isoenzyme PKM2 (a glycolytic rate-limiting enzyme) is expressed in a variety of cells, particularly tumor cells [ 61 ]. The m 6 A eraser, FTO, accelerates translation and promotes malignant biological behavior of HCC by triggering demethylation of PKM2 mRNA.…”

Exploration of the single-cell transcriptomic landscape identifies aberrant glomerular cell crosstalk in a murine model of WT1 kidney disease

“…Fittingly, R3hdml knockout in mice show elevated albuminuria, podocyte foot process effacement and GBM thickening. Pyruvate kinase ( Pkm , log 2 FC = 0.87) overexpression in podocytes protects against mitochondrial dysfunction in murine diabetic nephropathy 20 and conversely, its loss worsens albuminuria and podocyte injury in an adriamycin model of focal segmental glomerulosclerosis (FSGS) 21 . Cdkn1c (log 2 FC = 1.04), encoding p57, is associated with podocyte proliferation in animal models of podocyte injury 22,23 and patients with proliferative glomerular disease 24,25 , with upregulation of p57 in cultured podocytes being associated with reduced proliferation rates 22 .…”

“…Fittingly, R3hdml knockout in mice show elevated albuminuria, podocyte foot process effacement and GBM thickening. Pyruvate kinase (Pkm, log2FC = 0.87) overexpression in podocytes protects against mitochondrial dysfunction in murine diabetic nephropathy 20 and conversely, its loss worsens albuminuria and podocyte injury in an adriamycin model of focal segmental glomerulosclerosis (FSGS) 21 .…”

From Physiology to Pathology: The Role of Mitochondria in Acute Kidney Injuries and Chronic Kidney Diseases

“…In addition, changes in metabolic fuel sources in diabetes and continuous ATP demand lead to an increase in oxygen consumption, which contributes to renal hypoxia [80]. Indeed, several studies published by King’s group have reported that elevated PKM2 in podocytes, a glycolysis metabolism enzyme, increased glucose flux and protected mitochondrial function, thus alleviating the progression of diabetic glomerular pathology [78, 81, 82]. A recent study highlighted the antiapoptotic potential of PKM2 by upregulating mitochondrial fusion protein Mfn1 [83].…”