Glomerulotubular disconnection in neonatal mice after relief of partial ureteral obstruction

Abstract

Ureteropelvic junction obstruction is a common cause of congenital obstructive nephropathy. To study the pathogenesis of nephropathy, a variable-partial, complete or a sham unilateral ureteral obstruction (UUO) was produced in mice within 2 days of birth. The obstruction was released in some animals at 7 days and kidneys harvested at 7-42 days of age for histologic and morphometric study. Renal parenchymal growth was stunted by partial UUO with the impairment proportional to the duration and severity of obstruction. Proximal tubule apoptosis and glomerulotubular disconnection led to nephron loss. Relief of partial UUO arrested glomerulotubular disconnection, resolved tubule atrophy, and interstitial fibrosis with remodeling of the renal architecture. Relief of severe UUO did not result in recovery. Compensatory growth of the contralateral kidney depended on the severity of obstruction. Our studies indicate that relief of moderate UUO will minimize nephron loss. Application of this technique to mutant mice will help develop future therapies to enhance nephron recovery.

Generation and Evolution of Atubular Glomeruli in the Progression of Renal Disorders

“…69,70 Tubular apoptosis and small crowded glomeruli are found also in kidneys of neonatal mice subjected to chronic partial UUO. 71 In this model, atubular glomeruli were readily identified by the absence of lectin-staining columnar parietal epithelial cells that normally extend from the proximal tubule onto Bowman's capsule in this species ( Figure 6, A and B). 71 Renal microdissection studies in children with obstructive uropathy reveal "beading" or segmentation and diverticula along the initial length of the proximal tubule ( Figure 7).…”

“…71 In this model, atubular glomeruli were readily identified by the absence of lectin-staining columnar parietal epithelial cells that normally extend from the proximal tubule onto Bowman's capsule in this species ( Figure 6, A and B). 71 Renal microdissection studies in children with obstructive uropathy reveal "beading" or segmentation and diverticula along the initial length of the proximal tubule ( Figure 7). 72 It is likely that progression of proximal tubular segmentation leads to fragmentation of the tubule, as shown in neonatal mice subjected to partial UUO ( Figure 6, C through E).…”

“…63 In children with obstructive ne- The PCT becomes disconnected from the glomerulus and continues to degenerate. 71 Bar ϭ 100 m in B and applies to all 10 panels in A and B; 25 m in D and applies to both C and D. 71 phropathy or reflux nephropathy, atubular glomeruli were found to contain immunoreactive renin, which may contribute to hypertension in these patients. 64 In a recent study of 61 children undergoing pyeloplasty for ureteropelvic junction obstruction, increased glomerular density and decreased proximal/distal size ratio emerged as correlates of severity of obstruction and postoperative functional decline.…”

“…72 It is likely that progression of proximal tubular segmentation leads to fragmentation of the tubule, as shown in neonatal mice subjected to partial UUO ( Figure 6, C through E). 71 Obstruction of single nephrons causes loss of proximal tubule epithelial cell microvilli, with reductions in the cells' mitochondria and basolateral interdigitations. 73 It is notable that tubular obstruction plays a role in the progression of polycystic kidney disease in rats.…”

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

“…[30][31][32][33][34][35] We used TUNEL labeling to assay apoptosis in kidneys obstructed for 1, 2, 3, 6, and 9 days. In sham-operated kidneys at all time points, TUNEL-positive cells were rare and scattered throughout the kidney (Figures 4a-c) and are indicative of the normal rate of cell turnover within the kidney.…”