Obstructive nephropathy: Insights from genetically engineered animals

Abstract

Congenital obstructive nephropathy is the primary cause for end-stage renal disease (ESRD) in children. An increasingly used animal model of obstructive nephropathy is unilateral ureteral obstruction (UUO). This model mimics, in an accelerated manner, the different stages of obstructive nephropathy leading to tubulointerstitial fibrosis: cellular infiltration, tubular proliferation and apoptosis, epithelial-mesenchymal transition (EMT), (myo)fibroblast accumulation, increased extracellular matrix (ECM) deposition, and tubular atrophy. During the last decade genetically modified animals are increasingly used to study the development of obstructive nephropathy. Although the use of these animals (mainly knockouts) has highlighted some pitfalls of this approach (compensation by closely related gene products, absence of temporal knockouts) it has brought important information about the role of specific gene-products in the pathogenesis of obstructive nephropathy. Besides confirming the important pathologic role for angiotensin II (Ang II) and transforming growth factor-beta (TGF-beta) in obstructive nephropathy, these animals have shown the complexity of the development of tubulointerstitial fibrosis involving a large number of closely functionally related molecules. More interestingly, the use of these animals has led to the discovery of unexpected and contradictory roles (both potentially pro- and antifibrotic) for Ang II, for ECM degrading enzymes matrix metalloproteinase 9 (MMP-9) and tissue plasminogen activators (PAs), for plasminogen activator inhibitor 1 (PAI-1), and for the adhesion molecule osteopontin (OPN) in obstructive nephropathy. Further use of these animals, especially in combination with pharmacologic tools, should help to better identify potential antifibrotic strategies in obstructive nephropathy.

Basigin/CD147 Promotes Renal Fibrosis after Unilateral Ureteral Obstruction

“…43,50 A number of studies have revealed major pathways leading to the development of renal fibrosis after UUO surgery: the initial event is interstitial infiltration of macrophages that produce cytokines responsible for fibroblast proliferation and activation. After UUO operation, macrophages infiltrate the tubulointerstitial space from blood vessels and become a major source of cytokines, such as TGF-␤.…”

“…42,43 Both Bsg ϩ/ϩ and Bsg Ϫ/Ϫ mice exhibited only slight macrophage infiltration at day 3 (Figure 2A). Macrophage infiltration into the interstitium became prominent at day 7, and increased more at day 14 ( Figure 2, A and B).…”

Beneficial effects of a combination of Rho-kinase inhibitor and ACE inhibitor on tubulointerstitial fibrosis induced by unilateral ureteral obstruction

“…24 At present, one of the most important molecular mechanism of renal fibrosis in this model is increase of TGF-b. [23][24][25] Earlier studies have shown that macrophage/monocyte infiltration occurred in the kidney 4 h after acute ureteral obstruction and its peak response occurred at 24 h after UUO and stabilized thereafter. 26 Another study also showed a highly significant correlation between the increasing number of interstitial macrophage/monocyte and the cortical TGF-b mRNA levels.…”

“…Given that collagen accumulation is responsible for renal fibrosis, 22 the renal fibrosis in UUO can be explained, at least in part, by the enhancing of the TGF-b/collagen pathway. 23 A great deal of investigation has been conducted to understand the cellular and molecular mechanisms of renal fibrosis in this model. 24 At present, one of the most important molecular mechanism of renal fibrosis in this model is increase of TGF-b.…”

Hsp70/nitric oxide relationship in apoptotic modulation during obstructive nephropathy

“…These animals have shown the complexity of apoptosis and tubulointerstitial fibrosis development involving a large number of closely related molecules functionally. In addition, the recent development of mechanical stretch in cultured epithelial cells that mimics renal tubular distention has led to the discovery of unexpected and contradictory roles of principal apoptosis modulating factors (Bascands and Schanstra 2005).…”