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 patients with type 1 and type 2 diabetes. Here, mice with PKM2 overexpression specifically in podocytes (PPKM2Tg) were generated to uncover the renal protective function of PPKM2Tg as a potential therapeutic target that prevented elevated albumin/creatinine ratio (ACR), mesangial expansion, basement membrane thickness, and podocyte foot process effacement after 7 months of streptozotocin-induced (STZ-induced) diabetes. Furthermore, diabetes-induced impairments 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 glomerular filtration (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 podocytes. These findings demonstrate that PKM2 structure and enzymatic activation in podocytes can preserve the entire glomerular mitochondrial function against toxicity of hyperglycemia via paracrine factors such as VEGF and prevent DN progression.
Highlights
Diabetic nephropathy (DN) is the major cause of end-stage kidney disease (ESKD) in people with diabetes, affecting 30% of patients with diabetes [1–4]
We demonstrate that overexpression of pyruvate kinase M2 (PKM2) targeted to podocytes can prevent multiple molecular, metabolic functional, and pathological changes induced by diabetes in the whole glomeruli
Our findings show that targeting PKM2 and glucose metabolism in the podocyte selectively could normalize glycolytic and mitochondrial metabolism of the whole glomeruli, even in the presence of chronic diabetes and hyperglycemia
Summary
Diabetic nephropathy (DN) is the major cause of end-stage kidney disease (ESKD) in people with diabetes, affecting 30% of patients with diabetes [1–4]. Multiple risk factors are associated with DN, including hypertension, hyperglycemia, insulin resistance, dyslipidemia, and familial clustering [5–10]. In people with type 1 diabetes (T1D), hyperglycemia is the major risk factor for DN since glycemic control can prevent and delay its progression [10–13]. There is interest in identifying mechanisms of toxic effects by hyperglycemia, such as the disruption of filtration barrier due to abnormalities of glomerular podocytes, endothelial and mesangial cells, and glomerular basement membranes (GBM) [5]. Podocyte dysfunction and apoptosis have generated a great deal of interest, since their pedicels are critical for the formation and maintenance of glomerular filtration barrier [14]. This study is focused on the regulation of glycolysis and mitochondrial metabolism of podocytes and its effects on whole glomerular metabolism and pathology in normal and hyperglycemic conditions
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