Hyperhexosemia induced functional and structural changes in the kidneys: role of endothelins.
OBJECTIVE
Glomerular basement membrane (GBM) thickening and mesangial matrix expansion are characteristic features of diabetic nephropathy. The present study investigates the role of endothelins (ETs) in the pathogenesis of such changes in diabetic nephropathy.


METHODS
Diabetic (streptozotocin-induced, 65 mg/kg), galactose-fed (30%) and control animals were followed up for 1 and 6 months. Animal groups also included diabetic and galactose fed animals on dual ET(A)/ET(B) receptor antagonist bosentan (100 mg/kg). A semi-quantitative reverse transcription polymerase chain reaction method was used to quantify mRNA expression of ET-1, ET-3, ET(A), ET(B), fibronectin and collagen alpha2(IV). Histological analyses of the kidneys and ET-1, ET-3 and fibronectin immunohistochemistry were performed. Morphometric assessment of the GBM after 6 months was performed.


RESULTS
Diabetes increased mRNA expression of ET-1, ET-3, ET(A), ET(B), fibronectin and collagen alpha2(IV) after one and six months. In contrast, although increased ET(A) and ET(B) mRNAs were present following galactose feeding both at 1 and 6 months, ET-1, ET-3, fibronectin and collagen alpha2(IV)mRNAs were increased after 6 months. Both diabetes and galactose feeding caused increased GBM thickening. Furthermore, diabetes caused an increase in mesangial matrix production. Bosentan prevented increased fibronectin and collagen alpha2(IV) mRNA expression, increased mesangial matrix deposition and GBM thickening.


CONCLUSIONS
This study has demonstrated that diabetes and galactose feeding induced functional and structural changes in the kidney are mediated via ETs.
Chen
S
S
Department of Pathology, University of Western Ontario, London, Ontario, Canada.
Evans
T
T
Deng
D
D
Cukiernik
M
M
Chakrabarti
S
S
D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001485:Basement Membrane / Q000648:ultrastructure; D000077300:Bosentan; D003094:Collagen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D005690:Galactose / Q000008:administration & dosage / Q000097:blood*; D006801:Humans; D007668:Kidney / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000627:therapeutic use
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D005353:Fibronectins; D017466:Receptors, Endothelin; D013449:Sulfonamides; D003094:Collagen; D000077300:Bosentan; D005690:Galactose