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Published ahead of print on October 1, 2009
J Am Soc Nephrol 20: 2380-2388, 2009
© 2009 American Society of Nephrology
doi: 10.1681/ASN.2008111138
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BASIC RESEARCH

The PPAR{gamma} Agonist Pioglitazone Ameliorates Aging-Related Progressive Renal Injury

Hai-Chun Yang*,{dagger}, Sebastien Deleuze*, Yiqin Zuo*, Sebastian A. Potthoff*,{ddagger}, Li-Jun Ma* and Agnes B. Fogo*

*Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee;
{dagger}Division of Nephrology, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai, China; and
{ddagger}Department of Internal Medicine/Nephrology, Heinrich-Heine-University, Duesseldorf, Germany

Correspondence: Dr. Agnes B. Fogo, MCN C3310, Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232. Phone: 615-322-3070; Fax: 615-343-7023; E-mail: agnes.fogo{at}vanderbilt.edu

Received for publication November 3, 2008. Accepted for publication July 16, 2009.

Peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) agonists not only improve metabolic abnormalities of diabetes and consequent diabetic nephropathy, but they also protect against nondiabetic chronic kidney disease in experimental models. Here, we found that the PPAR-{gamma} agonist pioglitazone protected against renal injury in aging; it reduced proteinuria, improved GFR, decreased sclerosis, and alleviated cell senescence. Increased local expression of PPAR-{gamma} paralleled these changes. Underlying mechanisms included increased expression of klotho, decreased systemic and renal oxidative stress, and decreased mitochondrial injury. Pioglitazone also regulated p66Shc phosphorylation, which integrates many signaling pathways that affect mitochondrial function and longevity, by reducing protein kinase C-β. These results suggest that PPAR-{gamma} agonists may benefit aging-related renal injury by improving mitochondrial function.


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