Obstructive nephropathy: towards biomarker discovery and gene therapy

Abstract

Obstructive nephropathy is a major cause of renal failure, particularly in infants and children. Cellular and molecular mechanisms responsible for the progression of the tubular atrophy and interstitial fibrosis-processes that lead to nephron loss-have been elucidated in the past 5 years. Following urinary tract obstruction and tubular dilatation, a cascade of events results in upregulation of the intrarenal renin-angiotensin system, tubular apoptosis and macrophage infiltration of the interstitium. This is followed by accumulation of interstitial fibroblasts through proliferation of resident fibroblasts and epithelial-mesenchymal transformation of renal tubular cells. Under the influence of cytokines, chemokines and other signaling molecules produced by tubular and interstitial cells, fibroblasts undergo transformation to myofibroblasts that induce expansion of the extracellular matrix. The cellular interactions that regulate development of interstitial inflammation, tubular apoptosis and interstitial fibrosis are complex. Changes in renal gene expression and protein production afford many potential biomarkers of disease progression and targets for therapeutic manipulation. These include signaling molecules and receptors involved in macrophage recruitment and proliferation, tubular death signals and survival factors, and modulators of epithelial-mesenchymal transformation. Targeted gene deletion and various forms of gene therapy have been used in experimental obstructive nephropathy, mostly rodent models of unilateral ureteral obstruction or cell culture techniques. Further refinement of these models is needed to develop a matrix of biomarkers with clinical predictive value, as well as molecular therapies that will prevent or reverse the renal structural and functional consequences of obstructive nephropathy.

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…To a certain extent TECs can compensate for stress, as in selective albuminuria, however, if the injury gets more pronounced, the adaptive response will lead to fibrosis and progressive kidney disease (126). Processes involved in mediating the profibrotic response include TEC senescence (6,127,128), apoptosis (129,130), autophagy (131,132), and endoplasmic reticulum stress (133,134), however, many of these processes can also have beneficial effects under certain conditions (135,136). Another process leading to profibrotic activation of TECs is cell cycle arrest (137).…”

Hsp70/nitric oxide relationship in apoptotic modulation during obstructive nephropathy

“…It is a complex renal disorder that begins with hydrodynamic and hemodynamic responses, leading to cellular changes in all renal compartments, and finally to interstitial fibrosis and tubular atrophy (Chevalier 2006). Renal fibrogenesis initiates at a very early stage after ureteral obstruction and progresses rapidly.…”

“…Because of the significant role of apoptosis in the pathogenesis of renal cellular injury resulting from urinary tract obstruction, factors regulating the renal apoptotic response have been studied (Chevalier 2006). Stretching of the renal tubular cells by increased hydrostatic pressure provides a powerful mechanical stimulus to apoptosis in the obstructed kidney (Nguyen et al 2000;Manucha et al 2007).…”

Urinary tract obstruction in the mouse: the kinetics of distal nephron injury

“…[1][2][3][4] We have previously demonstrated that fetal obstruction in the human and primate kidney causes substantial medullary injury, including interstitial expansion, peritubular a smooth muscle actin (aSMA) collar formation, and collecting duct epithelial dysfunction. 1-3 Additional work is required to further identify how medullary and collecting duct injury contributes to and modulates the pathophysiology and progression of injury following obstruction.The rodent unilateral ureteric obstruction (UUO) models are the best-described models of urinary tract obstruction [5][6][7][8][9][10][11][12][13][14][15][16] and are widely used due to their ease of manipulation and the availability of transgenic animals. These models are predominantly postnatal models with much of the work focused on the role of the proximal convoluted tubule and on late time points in which the interstitial and fibrotic responses predominate.…”

“…The rodent unilateral ureteric obstruction (UUO) models are the best-described models of urinary tract obstruction [5][6][7][8][9][10][11][12][13][14][15][16] and are widely used due to their ease of manipulation and the availability of transgenic animals. These models are predominantly postnatal models with much of the work focused on the role of the proximal convoluted tubule and on late time points in which the interstitial and fibrotic responses predominate.…”