Upregulation of Endothelin A Receptor Sites in the Rabbit Diabetic Kidney: Potential Relevance to the Early Pathogenesis of Diabetic Nephropathy

Abstract

Background/Aim: Nephropathy is an important complication of diabetes mellitus (DM). The plasma endothelin 1 (ET-1) levels are increased in DM, and ET-1 may cause deleterious effects on renal function. We, therefore, investigated whether changes in ET receptors occur in the DM rabbit kidney. Methods: Nine adult New Zealand White rabbits were injected with alloxan, of which 6 became diabetic; the other 3 acted as alloxan-treated controls. Six age-matched healthy rabbits served as controls. At 6 months, following cervical dislocation, the kidneys were removed, and sections (cortex and medulla) were incubated with ET_A and ET_B radioligands to produce low- and high-resolution autoradiographs. Immunohistochemical localization of ET-1 immunoreactivity was also performed. Results: There was greater ET_A and ET_B receptor binding in the control (ET_A p = 0.0003; ET_B p < 0.0001) and DM (ET_A p = 0.001; ET_B p < 0.0001) rabbits in the medulla as compared with the cortex. DM kidneys showed a significant increase in ET_A, but not ET_B, binding in the cortex (p < 0.0001) and in the medulla (p < 0.0001). High-resolution autoradiographs revealed striking [¹²⁵I]-ET-1 receptor binding predominantly to the glomeruli. Immunohistochemistry revealed dense ET-1 immunoreactivity associated with the renal tubules, but the glomeruli exhibited no staining. Alloxan-treated controls had similar results to age-matched controls. Conclusion: There are regional differences in both ET_A and ET_B binding in control and DM kidneys. ET_A receptor binding sites are increased in the DM kidney (cortex and medulla). ET-1 may act in a paracrine fashion on the glomeruli. These changes may contribute to the pathogenesis of diabetic nephropathy.

Diabetes‐induced overexpression of endothelin‐1 and endothelin receptors in the rat renal cortex is mediated via poly(ADP‐ribose) polymerase activation

“…Our renal ET-1 values are in the range of those reported by four other groups (52)(53)(54)(55) who employed different techniques, that is, radioimmunoassay (RIA) or reverse-phase HPLC coupled to RIA. Increased gene expression of both ET(A) and ET(B) receptors in the renal cortex of rats with one-month diabetes in our study is consistent with another study in the rat model (51), as well as increased ET (A) receptor binding in rabbits with short-term diabetes compared with controls (56). ISO treatment caused an essential correction of both ET-1 concentration and ET-1, ET(A) and ET(B) mRNA abundance, whereas ABA caused a trend towards normalization of these variables, consistent with a weaker effect on tubular poly (ADPribosyl)ation.…”

“…ISO treatment caused an essential correction of both ET-1 concentration and ET-1, ET(A) and ET(B) mRNA abundance, whereas ABA caused a trend towards normalization of these variables, consistent with a weaker effect on tubular poly (ADPribosyl)ation. These data are consistent with primarily tubular localization of ET-1 in the renal cortex in early diabetes (56). In contrast to the report (51), we did not find any up-regulation of E-3 mRNA in the kidney of rats with 1-month duration of STZ-diabetes.…”

The endothelin receptor antagonist avosentan ameliorates nephropathy and atherosclerosis in diabetic apolipoprotein E knockout mice

“…There is increasing evidence to suggest there is altered expression and distribution of various components of the endothelin system in diabetic nephropathy [18,19]. The mechanism by which ET-1 promotes renal and vascular injury in diabetes is an area of active and ongoing investigation.…”

Effect of the antiplatelet drug dilazep dihydrochloride on urinary podocytes in patients in the early stage of diabetic nephropathy.

“…Diabetic nephropathy is characterized by hypertrophy of both glomerular and tubular structures, thickening of the basement membranes, and progressive accumulation of the extracellular matrix in the mesangium as well as in the interstitium (11,12). Despite a reported demonstration that high glucose stimulates extracellular matrix synthesis in cultured visceral glomerular epithelial cells (13), the growth profile of these cells in diabetic patients has not been investigated.…”