TUBULOINTERSTITIAL DISEASE IN AGING - EVIDENCE FOR UNDERLYING PERITUBULAR CAPILLARY DAMAGE, A POTENTIAL ROLE FOR RENAL ISCHEMIA

Aging is associated with a progressive decline in renal function and t he development of glomerulosclerosis and interstitial fibrosis. Althou gh many studies have addressed the cellular mechanisms of age-related glomerulosclerosis, less is known about the tubulointerstitial fibrosi s. In this study, aging (24 mo) rats develop tubulointerstitial fibros is characterized by tubular injury and focal tubular cell proliferatio n, myofibroblast activation, macrophage infiltration with increased im munostaining for the adhesive proteins osteopontin and intercellular a dhesion molecule-1, and collagen IV deposition. Aging rats demonstrate d immunostaining for endothelial nitric oxide synthase (eNOSIII) in re nal tubular epithelial cells and infiltrating mononuclear cells in are as of tubulointerstitial injury, with a relative loss of staining of t he peritubular capillaries compared with young rats. The aging rats al so displayed focal loss of peritubular capillaries (as noted by focall y decreased RECA-1 and OX-2 staining) in areas of tubulointerstitial i njury. The areas of fibrosis and hypocellularity were associated with increased apoptosis of tubular and interstitial cells compared with yo ung (3 mo) rats (25.4 +/- 5.3 versus 3.5 +/- 2.5 TUNEL-positive cells/ 0.25 mm(2) in old versus young rats, P = 0.0001). It is concluded that tubulointerstitial fibrosis in aging is an active process associated with interstitial inflammation and fibroblast activation. The progress ive loss of cells in areas of fibrosis may be due to accelerated apopt osis. Furthermore, the tubulointerstitial injury may be the consequenc e of ischemia secondary to peritubular capillary injury and altered eN OS expression.