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Published ahead of print on February 16, 2005
J Am Soc Nephrol 16: 1005-1012, 2005
© 2005 American Society of Nephrology
doi: 10.1681/ASN.2004080674
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Pathophysiology of Renal Disease and Progression

Effects of Proteasome Inhibition on the Kidney in Experimental Hypercholesterolemia

Alejandro R. Chade*, Joerg Herrmann{dagger}, Xiangyang Zhu*, James D. Krier*, Amir Lerman{dagger} and Lilach O. Lerman*,{dagger}

Department of Internal Medicine, Divisions of * Nephrology and Hypertension and {dagger} Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota

Address correspondence to: Dr. Lilach O. Lerman, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905. Phone: 507-266-9376; Fax: 507-266-9316; E-mail: lerman.lilach{at}mayo.edu

Received for publication August 16, 2004. Accepted for publication December 29, 2004.

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-{kappa}B. 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-{kappa}B, 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-{kappa}B 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.




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