Mechanisms of Tubulointerstitial Injury in the Kidney: Final Common Pathways to End-stage Renal Failure

Abstract

There are many different glomerular disorders, including glomerulonephritis, diabetic nephropathy, and hypertensive nephrosclerosis. However, once glomerular damage reaches a certain threshold, the progression of renal disease is consistent and irreversible. Recent studies emphasized the crucial role of tubulointerstitial injury as a mediator of progression of kidney disease. One common mechanism that leads to renal failure via tubulointerstitial injury is massive proteinuria. Accumulating evidence suggests critical effects of filtered macromolecules on tubular cells, including lysosomal rupture, energy depletion, and tubular injury directly induced by specific components such as complement components. Another common mechanism is chronic hypoxia in the tubulointerstitium. Tubulointerstitial damage results in the loss of peritubular capillaries, impairing blood flow delivery. Interstitial fibrosis also impairs oxygen diffusion and supply to tubular cells. This induces chronic hypoxia in this compartment, rendering a vicious cycle. Development of novel therapeutic approaches against these final common pathways will enable us to target any types of renal disease. (Internal Medicine 43: 9-17, 2004)

Renoprotective effects of an angiotensin II receptor blocker in experimental model rats with hypertension and metabolic disorders

“…In support of this, Ang II has been shown to induce marked glomerular sclerosis 27 with cell proliferation of the glomerular mesangium, 28 vascular endothelium, 29 tubular epithelium 30 and the vascular smooth muscle. 31 Ang II causes podocyte injury by increasing glomerular capillary pressure through a selective constriction of efferent arterioles.…”

The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

“…These changes contribute to increased glomerular filtration rate, proteinuria, systemic hypertension and the loss of renal function [4]. Histologically, DN is characterised by an accumulation of extracellular matrix (ECM) in both the glomerular mesangium and tubular interstitum, culminating in excessive renal scarring and a decline in excretory function [4][5][6][7]. Renal fibrosis is evidenced by glomeruosclerosis, tubulinterstitial fibrosis (TIF), infiltration of inflammatory mediators and the activation of alpha-smooth muscle actin (α-SMA)-positive myofibroblasts [6] [8].…”

“…Consequently, progressive tubulointerstitial fibrosis, in part mediated by EMT, represents the final common pathway leading to renal failure in diabetic nephropathy [7].…”

Implication of dysregulation of the canonical wingless-type MMTV integration site (WNT) pathway in diabetic nephropathy

“…The renal lesions in type 1 and type 2 diabetes are similar [2], and involve multiple cell types, including glomerular podocytes, mesangial cells and tubular epithelial cells [3]. Although the glomerulus has been the focus of intensive investigation, recently tubulo-interstitial injury has drawn more attention and interest in diabetic nephropathy research [4,5]. Hyperglycaemia-induced AGE, cytokines, chemokines, growth factors and oxidative stress have been shown to mediate renal damage in human and experimental diabetes [1,6].…”