Ultrastructure of Tubular Epithelial Cells in Response to Microembolism-Induced Chronic Ischemic Injury in Rats

Abstract

Background: Loss of polarization of proximal tubular epithelial cells (PTECs) with detachment is known as an early response of PTEC to acute ischemia during acute tubular necrosis. However, the early morphologic changes of PTECs to chronic ischemic injury are not clear. We previously reported that rat renal microembolism induced chronic tubulointerstitial ischemia and extensive proximal tubular atrophy. Among atrophic tubules, some tubules showed a peculiar pattern mixed with intact and atrophic epithelial cells, which was thought to be the earliest feature leading to atrophic tubules. Methods: Chronic ischemic injury was induced by the left renal perfusion of microspheres after removal of the right kidney in rats. The ultrastructual changes, especially focusing on the process of tubular atrophy, are examined by electron microscopy after 4, 8 and 12 weeks. Results: Early changes in PTECs showed slight simplification or dedifferentiation such as loss or diminution of basolateral infolding and microvilli. Moderately simplified PTECs were partially detached from the tubular basement membrane (TBM) with matrix production in the detached spaces but maintained cell-cell contacts between PTECs. In the advanced stage, severely simplified PTECs showed complete detachment from TBM and more atrophic features characterized by cobblestone appearance with a uniform attachment between cells. In concert with these PTEC changes, accumulation of interstitial fibroblast-like cells (FLCs) with collagenous matrices could be found first in the interstitial spaces and later in the spaces where PTECs detached from TBM. Conclusion: Our results suggest that microembolism-induced chronic ischemic injury induces PTEC dedifferentiation and detachment from TBM with matrix production in concert with FLC activation, resulting in tubulointerstitial damage characterized by tubular atrophy and renal fibrosis.