Urinary tract obstruction.
Angiotensin II plays a pivotal role in the progression of renal diseases, including obstructive nephropathy. Increasing levels of angiotensin II in obstructive nephropathy upregulate the expression of several factors: transforming growth factor-beta1 (TGF-beta1), tumor necrosis factor-alpha (TNF-alpha), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF-1), osteopontin, vascular cell adhesion molecule-1 (VCAM-1), nuclear factor-kappaB (NF-kappaB), monocyte chemoattractant peptide-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), and CD14 among others. Local production of TGF-beta, by intrinsic renal cells or by macrophages invading the kidney, is a key mediator of renal fibrosis. Activation of TGF-beta stimulates endothelin production. Endothelin, in turn, is a potent stimulus for fibrogenesis. Oxidative stress, fueled in part by angiotensin II, upregulates the expression of adhesion molecules, chemoattractant compounds and cytokines. Sustained obstructive nephropathy leads to apoptosis of tubular epithelial cells. Several factors and genes involved in apoptosis have been described. Nuclear factor kappa-B is involved in the transcriptional regulation of genes present in several organs, including the kidney. NF-kappaB is activated in the setting of ureteral obstruction. Administration of angiotensin-converting enzyme (ACE) inhibitors decreased significantly the activation of NF-kappaB in the obstructed kidney. Studies in neonatal rats indicate that chronic ureteral obstruction decreases the expression of epidermal growth factor (EGF). Replacement of this factor decreased apoptosis and reduced the expression of vimentin, clusterin, and TGF-beta. The administration of IGF-1 also lessened the tubular and interstitial pathology in the setting of ureteral obstruction. A spectrum of urinary tract malformations have been described. The utility of certain markers such as fetal serum beta(2) microglobulin as a predictor of postnatal renal function in bilateral uropathies has been described. A number of pharmacologic interventions that ameliorate the increased expansion of the interstitial volume, decrease the expression of TGF-beta, and down-regulate the production of extracellular matrix and the infiltration of the interstitium by macrophages have been described. Drugs used include ACE inhibitors, administration of arginine, administration of osteogenic protein-1, Pirferidone, and so on. It is likely that in the next decade advances in genetic manipulations and new drug therapies may forestall the development of fibrosis in the setting of urinary tract obstruction.
Klahr
S
S
Department of Medicine, Barnes-Jewish Hospital at Washington University School of Medicine, St. Louis, MO 63110-1092, USA. sklahr@imgate.wustl.edu
D000804:Angiotensin II / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D005355:Fibrosis; D006801:Humans; D016328:NF-kappa B / Q000502:physiology; D018384:Oxidative Stress; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D015854:Up-Regulation; D014517:Ureteral Obstruction / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*
D016328:NF-kappa B; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II