480-P: Reversal of Diabetic Nephropathy in T2D db/db Mouse Model by Systemic Pyruvate Kinase M2 (PKM2) Activation

Abstract

Mitochondrial abnormalities induced by diabetes have been postulated to cause several complications including nephropathy. Elevated expressions of enzymes for glycolysis and mitochondrial functions in the glomeruli have been associated with protection against the development of diabetic nephropathy of chronic duration. Activation of a glycolytic enzyme, pyruvate kinase M2 (PKM2), by a small molecule selective activator (TEPP-46) or its targeted overexpression to the podocytes in mice reversed glomerular mitochondrial dysfunction and pathology in insulin deficient diabetic mice. However, the effects of PKM2 activation to stop glomerular dysfunction and pathology have not been studied in animal models of type 2 diabetes (T2D). Thus, we studied the effect of activating glycolysis and mitochondrial metabolism with PKM2 activator, TEPP-46, in db/db mice (with obesity and hyperglycemia) and BLKS mice on regular diet (RD) or high fat diet (HFD). HFD feeding induced obesity in BLKS but did not cause changes in glomerular PKM activities or functions as measured by urinary albumin to creatinine ratio (ACR). Oral feeding with TEPP-46 did not affect body weight (BW), glucose tolerance, lipids, ACR, glomerular pathology in BLKS mice on RD or HFD. In contrast, db/db mice on RD had elevated BW and hyperglycemia that were significantly increased by HFD, which also induced loss of glomerular PKM2 protein expression and activities, elevations of gene expression for fibrosis (fibronectin, TGF-b), mesangial expansion and ACR after 3 months. Intervention with oral TEPP-46 treatment for 3 months, but not 1 month, after 3 months of diabetes and HFD, (total of 6 months of diabetes), improved significantly both glomerular PK activities and ACR, without lowering hyperglycemia and hyperlipidemia of the db/db mice. These findings support the idea that systemic activation of PKM2 can improve renal functions in both T1D and T2D. Disclosure R. St-Louis: None. J. Fu: None. K. Park: None. T. Shinjo: None. J. Ludeke: None. H. Yokomizo: None. Q. Li: None. E. Wolfson: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc.