Renal Structural and Functional Repair in a Mouse Model of Reversal of Ureteral Obstruction

Abstract

The end point of immune and nonimmune renal injury typically involves glomerular and tubulointerstitial fibrosis. Although numerous studies have focused on the events that lead to renal fibrosis, less is known about the mechanisms that promote cellular repair and tissue remodeling. Described is a model of renal injury and repair after the reversal of unilateral ureteral obstruction (UUO) in male C57bl/6J mice. Male mice (20 to 25 g) underwent 10 d of UUO with or without 1, 2, 4, or 6 wk of reversal of UUO (R-UUO). UUO resulted in cortical tubular cell atrophy and tubular dilation in conjunction with an almost complete ablation of the outer medulla. This was associated with interstitial macrophage infiltration; increased hydroxyproline content; and upregulated type I, III, IV, and V collagen expression. The volume density of kidney occupied by renal tubules that exhibited a brush border was measured as an assessment of the degree of repair after R-UUO. After 6 wk of R-UUO, there was an increase in the area of kidney occupied by repaired tubules (83.7 ؎ 5.9%), compared with 10 d UUO kidneys (32.6 ؎ 7.3%). This coincided with reduced macrophage numbers, decreased hydroxyproline content, and reduced collagen accumulation and interstitial matrix expansion, compared with obstructed kidneys from UUO mice. GFR in the 6-wk R-UUO kidneys was restored to 43 to 88% of the GFR in the contralateral unobstructed kidneys. This study describes the regenerative potential of the kidney after the established interstitial matrix expansion and medullary ablation associated with UUO in the adult mouse. R enal injury and repair comprises a delicate balance between cell loss and proliferation and extracellular matrix (ECM) accumulation and remodeling. Although many studies have focused on the cellular and molecular events that lead to the development of renal fibrosis, less is understood about the process of endogenous renal repair.We have characterized a model of reversal of unilateral ureteral obstruction (R-UUO) in the mouse to assess the regenerative potential of the kidney after interstitial matrix expansion and medullary ablation. UUO initiates a marked increase in numbers of interstitial macrophages that contribute to the cascade of events that lead to the development of fibrosis and renal cell loss. The facilitation and recruitment of macrophages into the renal interstitium is coupled to the upregulated expression of an array of chemokines and adhesion molecules (1,2). After R-UUO in the rat, both cortical (3) and medullary (4) interstitial macrophages are found to decrease gradually in number toward control values by 4 wk after release.A marked decline in GFR and renal plasma flow is observed by 24 h after UUO in dogs, rabbits, and rats (5-7). The duration of UUO and the extent of cell loss play a pivotal role in the recovery of GFR and subsequent renal remodeling and repair. Whereas short-term UUO in rats seems to be completely reversible (8), UUO for Ͼ72 h may lead to renal fibrotic and apoptotic changes culminating in a perm...

Colony-Stimulating Factor-1 Promotes Kidney Growth and Repair via Alteration of Macrophage Responses

“…39,40 Hydroxyproline values were then multiplied by a factor of 6.94 to extrapolate collagen content from each sample (because hydroxyproline represents ϳ14.4% of the amino acid composition of collagen). 41 Collagen concentration was then determined by dividing collagen content as a percentage of the dry weight tissue.…”

“…The other half of each kidney was digested for the detection of changes in interstitial collagen subtypes by SDS-PAGE analysis. 39,40 The pepsin-digested supernatant fluids were then analyzed on 5% (w/v) acrylamide gels with stacking gels of 3.5% (w/v) acrylamide. The ␣1(I) collagen chains were separated from the ␣1(III) chains by interrupted electrophoresis with delayed reduction of the disulfide bonds of type III collagen.…”

Stem cell options for kidney disease

“…For example, even after prolonged unilateral ureteric obstruction (UUO), involving considerable inflammation, tubular necrosis and apoptosis, the renal cortex can substantially remodel [9] (see Figure 1). Such postnatal repair has been proposed to involve the re-expression of genes previously critical to the development of the normal kidney.…”

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

“…Previous studies have demonstrated abnormal expression of Coll IV to be a marker of epithelial injury and tubular remodeling. 2,3,29 In sham-operated kidneys, Coll IV is localized to the basement membranes of all tubules and ducts of the outer medulla and cortex and surrounding the vasculature (Figure 3). Obstruction results in the expansion of the cortical and medullary interstitial space and in the disruption and duplication of Coll IV basement membranes that surround the adjacent tubules or ducts.…”