Obstructive Nephropathy

Abstract: TGF-β/Smad3 signaling promotes fibrosis, but the development of therapeutic interventions involving this pathway will require the identification and ultimate targeting of downstream fibrosis-specific genes In this study, using a microRNA microarray and real-time PCR, wild-type mice had reduced expression of miR-29 along with the development of progressive renal fibrosis in obstructive nephropathy In contrast, Smad3 knockout mice had increased expression of miR-29 along with the absence of renal fibrosis in the same model of obstruction In cultured fibroblasts and tubular epithelial cells, Smad3 mediated TGF-β(1)-induced downregulation of miR-29 by binding to the promoter of miR-29 Furthermore, miR-29 acted as a downstream inhibitor and therapeutic microRNA for TGF-β/Smad3-mediated fibrosis In vitro, overexpression of miR-29b inhibited, but knockdown of miR-29 enhanced, TGF-β(1)-induced expression of collagens I and III by renal tubular cells Ultrasound-mediated gene delivery of miR-29b either before or after established obstructive nephropathy blocked progressive renal fibrosis In conclusion, miR-29 is a downstream inhibitor of TGF-β/Smad3-mediated fibrosis and may have therapeutic potential for diseases involving fibrosis

Abstract: Interstitial fibrosis has a major role in the progression of renal diseases. Several animal models are available for the study of renal fibrosis. The models of aminonucleoside-induced nephrotic syndrome, cyclosporin nephrotoxicity, and passive Heyman nephritis are characterized by molecular and cellular events similar to those that occur in obstructive nephropathy. Additionally, inhibition of angiotensin-converting enzyme exerts salutary effects on the progression of renal fibrosis in obstructive nephropathy. Unilateral ureteral obstruction (UUO) has emerged as an important model for the study of the mechanisms of renal fibrosis and also for the evaluation of the impact of potential therapeutic approaches to ameliorate renal disease. Many quantifiable pathophysiological events occur over the span of 1 wk of UUO, making this an attractive model for study. This paper reviews some of the ongoing studies that utilized a rodent model of UUO. Some of the findings of the animal model have been compared with observations made in patients with obstructive nephropathy. Most of the evidence suggests that the rodent model of UUO is reflective of human renal disease processes.

Abstract: Obstructive nephropathy is a major cause of renal failure, particularly in newborn babies and children. After urinary tract obstruction, and under the influence of mechanical forces and cytokines produced by tubular cells and cells that have infiltrated the interstitium, resident fibroblasts undergo activation and myofibroblasts are generated from bone-marrow-derived cells, pericytes and endothelial cells. In addition, selected tubular epithelial cells can become fibroblast-like cells via epithelial-mesenchymal transition. This transition is characterized by downregulation of epithelial marker proteins such as E-cadherin, zonula occludens 1 and cytokeratin; loss of cell-to-cell adhesion; upregulation of mesenchymal markers including vimentin, alpha-smooth muscle actin and fibroblast-specific protein 1; basement membrane degradation; and migration to the interstitial compartment. All the events of epithelial-mesenchymal transition are strictly regulated by complex signaling pathways. Myofibroblasts and activated fibroblasts proliferate and produce large amounts of extracellular matrix, which accumulates in the tubular interstitium; together with tubular atrophy, this accumulation leads to interstitial fibrosis. This Review examines the molecular mechanisms of fibroblast activation and epithelial-mesenchymal transition, processes that seem to be promising targets for the prevention, or even reversal, of interstitial fibrosis and renal dysfunction associated with obstructive nephropathy.