Endothelin-1 receptor blockade prevents renal injury in experimental hypercholesterolemia

Alejandro R. Chade, Patricia Best, Martin G Rodriguez-Porcel, Joerg Herrmann, Xiangyang Zhu, Tatsuya Sawamura, Claudio Napoli, Amir Lerman, Lilach O Lerman

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

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-α-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-κB, transforming growth factor-β, and tubulointerstitial and perivascular trichrome staining. Conclusion. 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.

Original languageEnglish (US)
Pages (from-to)962-969
Number of pages8
JournalKidney International
Volume64
Issue number3
DOIs
StatePublished - Sep 1 2003

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Endothelin A Receptors
Hypercholesterolemia
Endothelins
Kidney
Wounds and Injuries
Isoprostanes
Oxidative Stress
Hemodynamics
Diet
Glomerular Filtration Rate
Class E Scavenger Receptors
Perfusion
Dinoprost
X Ray Computed Tomography
Nitric Oxide Synthase Type III
Transforming Growth Factors
Electrophoretic Mobility Shift Assay
Vasoconstrictor Agents
Endothelin-1
Nitric Oxide Synthase Type II

Keywords

  • Endothelin
  • Hypercholesterolemia
  • Kidney
  • Regional blood flow

ASJC Scopus subject areas

  • Nephrology

Cite this

Endothelin-1 receptor blockade prevents renal injury in experimental hypercholesterolemia. / Chade, Alejandro R.; Best, Patricia; Rodriguez-Porcel, Martin G; Herrmann, Joerg; Zhu, Xiangyang; Sawamura, Tatsuya; Napoli, Claudio; Lerman, Amir; Lerman, Lilach O.

In: Kidney International, Vol. 64, No. 3, 01.09.2003, p. 962-969.

Research output: Contribution to journalArticle

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AU - Chade, Alejandro R.

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AU - Rodriguez-Porcel, Martin G

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AU - Zhu, Xiangyang

AU - Sawamura, Tatsuya

AU - Napoli, Claudio

AU - Lerman, Amir

AU - Lerman, Lilach O

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AB - 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-α-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-κB, transforming growth factor-β, and tubulointerstitial and perivascular trichrome staining. Conclusion. 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.

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