Pathogenesis of Diabetic Nephropathy

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ABSTRACT Diabetic nephropathy (DN) is characterized by disturbances in metabolic & cellular signaling events leading to increased synthesis of ECM. They include accentuated flux of glucose intermediaries & polyols, aberrations in fuel sensing molecules, e.g., AMPK; and increased PKC activity, generation of nocuous AGEs, expression of MAP/ERK kinases and Smad proteins, profibrogenic cytokines & production of reactive oxygen species (ROS). The latter are regarded as central to the pathogenesis of DN. These signaling events have been studied in glomerular cells and information for tubular or interstitial cells is limited. Interestingly, tubulointerstitial changes correlate better with derangement in renal functional parameters; thus there is a legitimate need to define the biology of DN with respect to “diabetic tubulopathy”. In addition to a multitude of signaling events that affect the pathology of the glomerulus, a recently discovered glucuronate-xylulose (G-X) pathway, apparently relevant to diabetic nephropathy that is operative specifically in the tubular compartment, has received very little attention. Events of G-X pathway are initiated by myo-inositol oxygenase (MIOX), a tubular enzyme that has an increased expression in DN. During G-X events there are severe perturbations in NADPH:NADP+ & NAD+:NADH ratios, as a result there is a tremendous degree of "redox imbalance" and "NAD+ deficiency" leading to consequential adverse tubular homeostasis (JASN 2015, JBC 2016-1). Since MIOX promoter includes carbohydrate, oxidant/ antioxidant, osmotic and sterol response elements a cyclic stimulation of MIOX would be anticipated following hyperglycemia, lipidemia and chemical oxidant stress (JBC-2011, JBC 2016-2, JASN-2017) along with sustained up-regulation of MIOX and generation of ROS. Its regulation is also modulated by epigenetic modifications (AJP 2017). Keeping in perspective the above considerations we wish to explore the mechanisms involved in the biology of tubulo-interstitium using various genetically modified MIOX mice models. AIM I is to delineate various epigenetic mechanisms that modulate MIOX expression, using mice models of hyperglycemia and hyperlipidemia. DNA methylation/demethylation of MIOX promoter, histone methylation/demethylation and acetylation/decetylation in MIOX-TG and MIOX-KO mice will be investigated and correlated with the extent of tubulointerstitial injury. AIM II is to delineate mechanisms that accentuate tubulointerstitial injury in MIOX-TG vs WT or -KO mice during hyperglycemia and AGEs' overload. Perturbations in renal functions, cellular redox, mitochondrial dynamics will be investigated. Rescue experiments will include cross-breeding Akita with MIOX-/- mice and various parameters reflecting amelioration of injury appraised. AIM III is to delineate mechanisms that augment renal injury in MIOX-TG vs WT & KO mice in hyperlipidemia. The events following MIOX over- expression, i.e., NAD+ deficiency, glutathione depletion and augmented generation of ROS, perturbations in sirtuins' activity, p-AMPK, PGC-1α, mitochondrial dynamics, ER stress and tubulo-interstitial fibrosis will be assessed. Rescue experiments will include cross-breeding of MIOX-/- with ob/ob and PPARαΔob/ob mice.