Association between endothelin-1 and collagen deposition in db/db diabetic mouse kidneys

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Abstract

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 an immunohistochemical 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.

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Methods

Metabolic, renal, and histopathological parameters in db/db mice. Male db/db (BKS.Cg-m+/+Leprdb) and db/m mice were used for all studies (Jackson Laboratories, Bar Harbor, ME) as previously described by our laboratory [10]. Manipulation and experiments were done in a barrier facility with gowning. To measure 24-h albumin and ET-1 excretion, mice were placed in individual diuresis cages (Nalgene, Rochester, NY) with access to water but not food for 24 h. Urinary albumin and ET-1 concentrations

Diabetes and glomerular injury in db/db mice

We measured ET-1 in 8- and 16-week db/db mice because 8-week-old mice have proteinuria but few histological changes, but 16-week-old mice show renal histopathological features of diabetic nephropathy including mesangial matrix expansion, thickening of the basement membrane, progressive proteinuria, and a decline in GFR [10], [21], [23], [24], [25], [26], [27]. As expected, diabetic mice in our study had higher blood glucose, glycosylated hemoglobin (GHb), and albuminuria (Table 1). Typical of

Discussion

ET-1 immunoreactivity was temporally and spatially associated with mesangial matrix expansion and glomerular collagen deposition in db/db mice. Moreover, renal ET-1 associated with collagen deposition in peritubular locations in the cortex. These results support a model in which ET-1 contributes to glomerular and peritubular changes in diabetic kidney injury.

Consistent with our study, a previous report [9] documented elevated ET-1 in glomeruli and in tubulointerstitial cells of the SHR/N-cp

Acknowledgments

This work was supported by a grant from the Rosenberg Foundation and by National Institutes of Health Grant DK62331.

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