Effects of proteasome inhibition on the kidney in experimental hypercholesterolemia

Alejandro R. Chade, Joerg Herrmann, Xiangyang Zhu, James D. Krier, Amir Lerman, Lilach O Lerman

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Hypercholesterolemia (HC) and atherosclerosis often accompany and aggravate renal disease. Proteasome inhibitors (PSI) can decrease proliferation and inflammation, likely by reducing activation of the proinflammatory NF-κB. However, chronic proteasome inhibition has never been demonstrated in the HC kidney. Four groups of pigs (n = 7 each) were studied after a 12-wk normal (N) or 2% HC diet alone or supplemented (N+PSI and HC+PSI) with MLN-273 (0.08 mg/kg subcutaneously twice weekly). Renal hemodynamics and function were quantified in vivo using electron-beam computed tomography at baseline and after vasodilator challenge using acetylcholine. Renal tissue was studied ex vivo using immunoblotting, PCR, and immunohistochemistry. Serum cholesterol was similarly elevated in HC and HC+PSI. Basal renal blood flow was similar among the groups, whereas GFR was decreased in both N+PSI and HC+PSI. The blunted renovascular and functional responses to acetylcholine in HC were normalized in HC+PSI (suggesting renal endothelial function improvement), which was accompanied by decreased renal endothelin, NF-κB, and augmented endothelial nitric oxide synthase expression. In parallel, HC+PSI animals also showed elevated NAD(P)H oxidase expression and circulating oxidized LDL, suggesting a potential for increased oxidative stress. This study shows that chronic PSI intervention in HC improves renal endothelial functional responses to challenge, possibly by modulating nitric oxide availability and endothelin. Furthermore, PSI may decrease intrarenal inflammation through modulation of the NF-κB pathway but may potentially increase oxidative stress, which warrants further investigation. This study may support a role for the ubiquitin/proteasome system in the kidney in HC and early atherosclerosis.

Original languageEnglish (US)
Pages (from-to)1005-1012
Number of pages8
JournalJournal of the American Society of Nephrology
Volume16
Issue number4
DOIs
StatePublished - 2005

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Proteasome Endopeptidase Complex
Hypercholesterolemia
Proteasome Inhibitors
Kidney
Endothelins
Acetylcholine
Atherosclerosis
Oxidative Stress
Inflammation
X Ray Computed Tomography
Nitric Oxide Synthase Type III
NADPH Oxidase
Renal Circulation
Ubiquitin
Vasodilator Agents
Immunoblotting
Nitric Oxide
Swine
Hemodynamics
Immunohistochemistry

ASJC Scopus subject areas

  • Nephrology

Cite this

Effects of proteasome inhibition on the kidney in experimental hypercholesterolemia. / Chade, Alejandro R.; Herrmann, Joerg; Zhu, Xiangyang; Krier, James D.; Lerman, Amir; Lerman, Lilach O.

In: Journal of the American Society of Nephrology, Vol. 16, No. 4, 2005, p. 1005-1012.

Research output: Contribution to journalArticle

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