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

Abstract

Congenital urinary tract obstruction is the single most important cause of childhood chronic kidney disease. We have previously demonstrated that human and primate fetal obstruction impairs the development, differentiation, and maturation of the kidney. Research using postnatal rodent models has primarily focused upon the role of proximal tubular injury, with few reports of collecting duct system pathology or the suitability of the postnatal models for examining injury to the distal nephron. We have employed the mouse unilateral ureteric obstruction (UUO) model and examined time points ranging from 1 to 14 days of obstruction. Many of the key features of fetal collecting duct injury are replicated in the postnatal mouse model of obstruction. Obstruction causes a sixfold increase in myofibroblast accumulation, two-to threefold dilatation of tubules of the distal nephron, 65% reduction of principal cell aquaporin 2 expression, 75% reduction of collecting duct intercalated cell abundance, and disruption of E-cadherin-and bcateninmediated collecting duct epithelial adhesion. Notably, these features are shared by the distal and connecting tubules. This work confirms that distal nephron pathology is a significant component of postnatal mouse UUO. We have highlighted the utility of this model for investigating collecting duct and distal tubule injury and for identifying the underlying mechanisms of the distal nephron's contribution to the repair and fibrosis. Congenital urinary tract obstruction is the single most important cause of chronic kidney disease in children. In the fetus, obstruction of urinary flow during the critical stages of renal nephrogenesis alters branching morphogenesis, decreases nephron endowment, and disrupts normal tubulointerstitial development. [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. [17][18][19][20] Although early changes in tubular hydrodynamics, tubular dilatation, and medullary injury have been briefly described following obstruction, our knowledge of the contributions of these factors and the potential cellular responses they invoke is lacking.We have previously demonstrated that the distal nephron, including the co...

Renal parenchyma impairment characterization in partial unilateral ureteral obstruction in mice with intravoxel incoherent motion‐MRI

“…In conclusion, our study showed, in a model of pUUO, a decrease in perfusion fraction using the IVIM technique, probably related to the reduction in glomeruli and perfusion rate, whereas D slow , reflecting cellularity, was not decreased significantly. These results might be explained by the very slow progression of fibrosis in the pUUO model, as has already been shown in the literature . Microperfusion could be an earlier biomarker of kidney impairment than molecular diffusion after pUUO.…”

“…These results might be explained by the very slow progression of fibrosis in the pUUO model, as has already been shown in the literature. 1,7 Microperfusion could be an earlier biomarker of kidney impairment than molecular diffusion after pUUO. Later time points would be beneficial to follow the establishment of fibrosis.…”

“…Therefore, the kinetics of observable kidney injuries is very rapid with diffuse fibrosis being established within only 2 weeks. 7 Despite the fact that the UUO model has been beneficial to improve the histopathological knowledge of various disease parameters, with this model, it is extremely difficult to develop new non-invasive imaging biomarkers with high specificity to microstructural change, as it is problematic to distinguish between the simultaneous biological 'signals' probed by the imaging method. 4 As a consequence, we decided to work with a partial unilateral ureteral obstruction (pUUO) model, which presents the advantage of creating a slower progression of the disease (i.e.…”

Uromodulin deficiency alters tubular injury and interstitial inflammation but not fibrosis in experimental obstructive nephropathy

“…Sections were processed as described by Hiatt et al. (). Secondary antibody used were Alexa‐Fluor conjugated (Molecular Probes/ThermoFisher Scientific).…”

Renal development in the fetus and premature infant

“…Postnatal ureteral obstruction also induces tubulointerstitial fibrosis in rodent models [23]. Whereas in humans it is not possible to eliminate the possibility that factors that affected the ureteral development independently lead to defects in renal development, it is clear that both UPJ and UVJ obstructions may result in obstructive uropathies and CKD in childhood [24].…”