Endothelin-1 has been implicated in diabetic kidney injury, but there are few firm data establishing the temporal and spatial expression of kidney endothelin-1 in diabetes. We performed in immunohstochemical and histopathological analysis to determine endothelin-1 peptide expression in the kidneys of diabetic db/db mice and non-diabetic db/m controls. Diabetic mice were studied at 8 weeks, before histological damage is evident, and again at 16 weeks, when significant glomerular injury has occurred. Urinary endothelin-1 was 6.2 and 3.6-fold higher in 8- and 16-week diabetic mice compared to age-matched controls (P < 0.01 db/db vs. db/m). Compared to non-diabetic kidneys, immunoreactive endothelin-1 was first elevated 2.5-fold (P = 0.02) in the tubulointerstitial compartment at 8-week and remained high (3.8-fold, P < 0.01) at 16 weeks. In contrast, glomerular endothelin-1 was elevated 3.2-fold (P = 0.03) only in 16-week diabetic mice. Glomerular and tubulointerstitial endothelin-1 Were unchanged in 8- and 16-week non-diabetic mice. Elevated endothelin-1 in diabetic mice associated temporally and spatially with collagen deposition, especially in the tubulointerstitial compartment. The localization of kidney endothelin-1 is consistent with a role for this peptide in renal fibrogenesis. These results also highlight the potential role of ET-1 in the pathogenesis of early tubulointerstitial changes in diabetes. (c) 2005 Elsevier Inc. All rights reserved.