Possible involvement of myofibroblasts in cellular recovery of uranyl acetate-induced acute renal failure in rats

Cellular recovery in acute renal failure is a form of wound healing. Fibrob last-like cells or myofibroblasts are involved in wound healing. We examine d the serial changes in tubular damage and origin and kinetics of regenerat ing cells in uranyl acetate-induced acute renal failure, with a special emp hasis on interstitial myofibroblasts, Acute renal failure was induced in ra ts by intravenous injection of uranyl acetate (5 mg/kg), All rats received bromodeoxyuridine intraperitoneally 1 hour before sacrifice, Serial changes in the distribution of tubular necrosis and bromodeoxyuridine-incorporated or vimentin-positive regenerating cells, and their spatial and temporal re lation to cu-smooth muscle actin-positive myofibroblasts as well as ED 1-po sitive monocytes/macrophages were examined. Necrotic tubules initially appe ared around the corticomedullary junction after uranyl acetate injection, t hen spread both downstream and upstream of proximal tubules, Peritubular al pha-smooth muscle actin-positive myofibroblasts appeared and extended along the denuded tubular basement membrane, establishing network formation thro ughout the cortex and the outer stripe of outer medulla at days 4 to 5, Tub ular regeneration originated in nonlethally injured tells in the distal end of S3 segments, which was confirmed by lectin and immunohistochemical stai ning using markers for tubular segment. Subsequently, upstream proliferatio n was noted along the tubular basement membrane firmly attached by myofibro blasts. During cellular recovery, no entry of myofibroblasts into the tubul ar lumen across the tubular basement membrane was noted and only a few myof ibroblasts showed bromodeoxyuridine positivity, The fractional area of alph a-smooth muscle actin-positive interstitium reached a peak level at day 7 i n the cortex and outer stripe of outer medulla, then gradually disappeared by day 15 and remained only around dilated tubules and in the expanded inte rstitium at day 21, ED 1-positive monocytes/macrophages were transiently in filtrated mainly into the region of injury. They did not show specific asso ciation with initially necrotic tubules, but some of them located in dose p roximity to regenerating tubules, Nonlethally injured cells at the distal e nd of proximal tubules are likely to be the main source of tubular regenera tion, and the transient appearance of interstitial myofibroblasts attached to the tubular basement membrane immediately after tubular necrosis might p lay a role in promoting cellular recovery in possible association with mono cytes/macrophages in uranyl acetate-induced acute renal failure.