Proximal Tubulopathy: Prime Mover and Key Therapeutic Target in Diabetic Kidney Disease

Abstract

The current view of diabetic kidney disease, based on meticulously acquired ultrastructural morphometry and the utility of measuring plasma creatinine and urinary albumin, has been almost entirely focused on the glomerulus. While clearly of great importance, changes in the glomerulus are not the major determinant of renal prognosis in diabetes and may not be the primary event in the development of diabetic kidney disease either. Indeed, advances in biomarker discovery and a greater appreciation of tubulointerstitial histopathology and the role of tubular hypoxia in the pathogenesis of chronic kidney disease have given us pause to reconsider the current "glomerulocentric" paradigm and focus attention on the proximal tubule that by virtue of the high energy requirements and reliance on aerobic metabolism render it particularly susceptible to the derangements of the diabetic state. Such findings raise important issues for therapeutic advances specifically targeting the pathophysiological perturbations that develop in this part of the nephron.

The Influence of the Tannic Acid on the Expression of the Connexins 45 in a Rat Kidney Damaged by the Chronic Hyperglycemia

“…Although we previously believed that that the renal damage in DM starts in glomerulus, recently we became aware that the PCT are initially damaged, and that their dysfunction is leading to the glomerular filtration membrane damage (Gilbert, 2017). Hence, the dynamics of the connexin expression in PTCs during different DM treatments could be of the extreme importance for the pathophysiology and treatment of the diabetic renal complications.…”

The relationships between markers of tubular injury and intrarenal haemodynamic function in adults with and without type 1 diabetes: Results from the Canadian Study of Longevity in Type 1 Diabetes

“…In the setting of hyperglycaemia, there is an increase in reabsorption of sodium and glucose as the result of upregulation of sodium‐glucose cotransporter 2 (SGLT2) in the proximal tubule . These increases in metabolic demand predispose proximal tubule epithelial cells (PTECs) to hypoxia which, in turn, stimulates a cascade of mediators leading to fibrosis and apoptosis . Second, the increase in glucose reabsorption that occurs in PTECs in the setting of diabetes also results in the generation of advanced glycosylation end‐products (AGEs).…”

“…There is increasing evidence to show that the renal tubule plays an important role in the pathogenesis of DKD. 2,17 Clinical studies in T1D and T2D demonstrate that RAAS inhibition is inadequate in preventing the progression of DKD. 18,19 Additionally, DKD can also occur without significant albuminuria, 20,21 which highlights the potential importance of diabetic tubulopathy and glomerulopathy in the development and progression of DKD.…”

An integrative systems biology approach for precision medicine in diabetic kidney disease

“…Although systems biology approaches have just recently been deployed to DKD, studies so far have made an impact by advancing the understanding of the molecular mechanisms underlying DKD pathogenesis. This has in turn lead to the identification of critical molecular abnormalities in DKD and to the development of novel treatments and potential molecular biomarkers …”