Upregulation of endothelin A receptor sites in the rabbit diabetic kidney: potential relevance to the early pathogenesis of diabetic nephropathy.
OBJECTIVE
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 [(125)I]-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.


CONCLUSIONS
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.
Khan
M A
MA
Department of Urology, Royal Free and University College Medical School (Royal Free Campus), University College, London, UK.
Dashwood
M R
MR
Mumtaz
F H
FH
Thompson
C S
CS
Mikhailidis
D P
DP
Morgan
R J
RJ
D000496:Alloxan; D000818:Animals; D001345:Autoradiography; D001381:Azepines / Q000378:metabolism / Q000494:pharmacology; D001786:Blood Glucose; D001806:Blood Urea Nitrogen; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism*; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000032:analysis; D016232:Endothelins / Q000378:metabolism / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D007457:Iodine Radioisotopes; D007668:Kidney / Q000737:chemistry / Q000378:metabolism; D008297:Male; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D011188:Potassium / Q000097:blood; D011817:Rabbits; D011869:Radioligand Assay; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000032:analysis / Q000378:metabolism*; D012964:Sodium / Q000097:blood; D015854:Up-Regulation / Q000502:physiology*
D001381:Azepines; D001786:Blood Glucose; D019332:Endothelin-1; D016232:Endothelins; D007457:Iodine Radioisotopes; D009842:Oligopeptides; D010446:Peptide Fragments; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C075771:BQ 3020; C087850:PD 151242; D000496:Alloxan; D012964:Sodium; D011188:Potassium