The thick ascending limb of Henle's loop ( TAL ) develops a specific and consistent structural lesion during perfusion of the isolated rat kidney that progresses from mitochondrial swelling at 15 min to complete cellular disruption at 90 min. Because it seemed possible that damage localized to this metabolically active portion of the nephron might be correlated with cellular transport, the histology of perfused kidneys was examined when transport activity in the TAL was varied. The fraction of TAL tubules showing severe damage (44 +/- 2% in kidneys perfused with glucose) was dramatically reduced by furosemide (7 +/- 2%; P less than 0.001). The lesion was eliminated by perfusion with ouabain or by preventing glomerular filtration. On the other hand, protection of TAL cells was not obtained with the proximal diuretic acetazolamide. These results suggest that the lesion of TAL cells that develops during perfusion of the isolated kidney is influenced by the work of cellular transport.