Peritubular Capillary Regression during the Progression of Experimental Obstructive Nephropathy

Abstract

Abstract. Injury to the renal microvasculature may be a major factor contributing to the progression of renal disease. Although severe disruption of peritubular capillaries (PTC) could lead to marked tubulointerstitial scarring, elucidation of that process remains incomplete. This study investigated the morphologic changes in PTC and their likely regulation by vascular endothelial growth factor (VEGF) during the progression of tubulointerstitial injuries. Unilateral ureteral obstruction was induced in Wistar rats by ligation of the left ureter, and the kidneys were then collected at selected times. PTC lumina and the expression of VEGF and its receptor Flk-1 were immunohistochemically detected. Morphologic changes in PTC endothelial cells were examined by using Ki67 staining, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick endlabeling, and electron-microscopic studies. In the first week of the disease period, immunohistochemical labeling of tubular VEGF intensified, with accompanying deformation and dilation of adjacent thrombomodulin (TM)-positive PTC lumina; an angiogenic response of endothelial cells was demonstrated with Ki67 and TM double-staining. During the subsequent 2 wk, tubular VEGF labeling decreased until it was virtually absent, an effect confirmed by Western blotting. Concomitantly, labeling of the VEGF receptor Flk-1 in PTC endothelial cells decreased and PTC lumina began to regress, demonstrating endothelial cell apoptosis (as detected in terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling and electron-microscopic studies). By the end of week 4, the numbers of TM-positive PTC lumina were significantly decreased in areas of marked tubulointerstitial scarring. These results suggest that PTC regression, involving an early, unsustained, angiogenic response followed by progressive endothelial cell apoptosis, could be a potential factor contributing to tubulointerstitial scarring in this unilateral ureteral obstruction model.Tubulointerstitial injuries are regarded as major determinants of progressive renal disease, and accumulating evidence suggests that the severity of tubulointerstitial changes could be the best indicator of the progression of renal dysfunction, regardless of the original insult (1-3). In the theories introduced to explain such changes, injury to the peritubular capillary (PTC) network of the kidney is regarded as a key factor (4,5). Recently, our group (6) and Kang et al. (7,8) indicated that rarefaction of PTC is crucial for the progression of tubulointerstitial injury. However, detailed characterization of this process has not been performed.Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen that acts via specific receptors, i.e., VEGF receptor-1 (Flt-1) and VEGF receptor-2 (Flk-1), to promote angiogenesis and increase vascular permeability (9 -12). Therefore, it has a potential role in a wide variety of situations, including liver fibrosis, tumor growth, and wound healing (13-15). In the kidney, VEGF is known ...

Role of Atrophic Tubules in Development of Interstitial Fibrosis in Microembolism-Induced Renal Failure in Rat

“…26 Similar explanation for an adverse effect of interstitial fibrosis on renal function was described by Morrissey and Klahr 27 in the review on NF-B regulation of renal fibrosis. Ohashi et al 28 demonstrated a significant decline in the number of the peritubular capillaries, followed by tubulointerstitial scarring in a rat experimental glomerulonephritis. In addition, Thomas et al 29 suggested a possibility that the tubulointerstitial injury in aging rats is the consequence of ischemia secondary to peritubular capillary injury and altered eNOS expression.…”

Peritubular Ischemia Contributes More to Tubular Damage than Proteinuria in Immune-Mediated Glomerulonephritis

“…Various experimental animal models have shown that hypoxia promotes tubulointerstitial fibrosis. 21,22 This study took advantage of the similar degree of proteinuria but differential glomerular damage seen in the model of anti-GBM GN in WT and FcRKO mice. It has been shown that significant loss of glomerular capillary space in WT mice is associated with marked reduction of peritubular capillary blood flow followed by a more severe degree of tubular hypoxia and thus more tubulointerstitial damage.…”

Mechanisms of Tubulointerstitial Injury in the Kidney: Final Common Pathways to End-stage Renal Failure

“…The significance of peritubular capillary damage, with subsequent tissue hypoxia and ischemia, has been emphasized by recent findings in animal models. Ohashi et al suggested an important role of peritubular capillary disruption in the development of renal disease and in the impairment of renal function in an anti-GBM nephritis model in Wistar Kyoto rats (60). Statistical analysis of this model revealed significant correlation between the peritubular capillary number and indicators of renal function.…”