Abstract
Diabetic kidney disease (DKD) is the leading cause of end stage renal disease (ESRD) in the USA. The pathogenesis of DKD is multifactorial and involves activation of multiple signaling pathways with merging outcomes including thickening of the basement membrane, podocyte loss, mesangial expansion, tubular atrophy, and interstitial inflammation and fibrosis. The glomerulo-tubular balance and tubule-glomerular feedback support an increased glomerular filtration and tubular reabsorption, with the latter relying heavily on ATP and increasing the energy demand. There is evidence that alterations in mitochondrial bioenergetics in kidney cells lead to these pathologic changes and contribute to the progression of DKD towards ESRD. This review will focus on the dialogue between alterations in bioenergetics in glomerular and tubular cells and its role in the development of DKD. Alterations in energy substrate selection, electron transport chain, ATP generation, oxidative stress, redox status, protein posttranslational modifications, mitochondrial dynamics, and quality control will be discussed. Understanding the role of bioenergetics in the progression of diabetic DKD may provide novel therapeutic approaches to delay its progression to ESRD.
Highlights
In Type 1 Diabetes (T1D), Diabetic kidney disease (DKD) progresses from an early glomerular hyperfiltration with microalbuminuria (ACR of 30–300 mg/g) to macroalbuminuria (ACR > 300 mg/g) while kidney function declines to end stage renal disease (ESRD)
We summarize data showing that diabetes affects all aspects of bioenergetic metabolism including switching the proportions of cell-specific fuel sources, causing enzymatic defects within the electron transport chain (ETC) complexes with consequences on ATP production and redox balance
Because glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was reported as inhibited in endothelial cells exposed to high glucose [81], and mitochondrial oxidative phosphorylation is depressed in diabetes, glycolytic intermediates follow alternative cytosolic non-ATP-producing pathways such as polyol pathway, activation of protein kinase C, and formation of advanced glycation end products and hexosamine pathway (Figure 2), which are recognized as central to diabetic chronic microvascular complications [81]
Summary
The glomerular hypertension and hyperfiltration with secondary albuminuria, thickening of the glomerular and tubular basement membranes, mesangial expansion, and podocyte loss are associated with glomerular sclerosis, tubular atrophy, and a progressively reduced kidney function with decreased eGFR [1]. Thickness of the tubular basement membrane is an early structural change observed in normoalbuminuric diabetic patients [29], and is proposed to be an accurate indicator of the severity of DKD [30]. An increase in the filtration fraction enhances the peritubular capillary oncotic pressure that favors proximal reabsorption As these processes take place via transcellular routes rather than paracellular pathways, they consume energy and involve multiple apical transporters driven by the basal Na-K ATPase. Inhibition of SGLT2 in the diabetic kidney reduces oxygen consumption in the proximal tubule and renal cortex due to lowering GFR [58,59]. Preservation of renal oxygenation and integrity of energy-producing structures are critical for maintaining kidney function in diabetes [61]
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