Endothelin-1 receptor blockade prevents renal injury in experimental hypercholesterolemia.
BACKGROUND
The potent vasoconstrictor endothelin-1 is involved in regulation of renal function, and is up-regulated in hypercholesterolemia (HC), a risk factor for renal disease that increases oxidative stress and impairs renal hemodynamic responses. However, the involvement of endothelin (ET) in this disease process is yet unknown.


METHODS
Regional renal hemodynamics and function in vivo were quantified in pigs at baseline and during infusion of acetylcholine using electron beam computed tomography after a 12-week normal diet (N = 6), HC diet (N = 6), and HC diet orally supplemented (4 mg/kg/day) with the selective ET receptor-A (ET-A) blocker ABT-627 (HC+ET-A, N = 6). Plasma levels of 8-epi-PGF2-alpha-isoprostanes, markers of oxidative stress, were measured using enzyme immunoassay, and renal tissue was studied ex vivo using Western blotting, electrophoretic mobility shift assay, and immunohistochemistry.


RESULTS
Total and low-density lipoprotein (LDL) cholesterol were similarly increased, but isoprostanes were decreased in HC+ET-A compared to HC alone. Basal renal perfusion was similar among the groups, while glomerular filtration rate (GFR) increased in HC+ET-A compared to HC. Stimulated perfusion and GFR were blunted in HC, but normalized in HC+ET-A. Moreover, ET blockade increased expression of endothelial nitric oxide synthase, and decreased endothelial expression of the oxidized-LDL receptor LOX-1, as well as tubular immunoreactivity of inducible nitric oxide synthase, nitrotyrosine, nuclear factor-kappaB, transforming growth factor-beta, and tubulointerstitial and perivascular trichrome staining.


CONCLUSIONS
ET-A blockade improves renal hemodynamic and function in HC, and decreases oxidative stress, and renal vascular and tubulointerstitial inflammation and fibrosis. These findings support a role for the endogenous ET system in renal injury in HC and atherosclerosis.
Chade
Alejandro R
AR
Department of Internal Medicine, Division of Hypertension, Mayo Clinic, Rochester, Minnesota, USA.
Best
Patricia J
PJ
Rodriguez-Porcel
Martin
M
Herrmann
Joerg
J
Zhu
Xiangyang
X
Sawamura
Tatsuya
T
Napoli
Claudio
C
Lerman
Amir
A
Lerman
Lilach O
LO
D000818:Animals; D000077868:Atrasentan; D001826:Body Fluids / Q000378:metabolism; D065130:Endothelin A Receptor Antagonists; D006439:Hemodynamics; D006937:Hypercholesterolemia / Q000150:complications*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000517:prevention & control*; D018384:Oxidative Stress / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology*; D012079:Renal Circulation; D013552:Swine
D065130:Endothelin A Receptor Antagonists; D011759:Pyrrolidines; D000077868:Atrasentan