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Identification of Functions of Peroxisome Proliferator-Activated Receptor in Proximal Tubules

Yuji Kamijo^*,, Kazuhiko Hora^,, Naoki Tanaka^*,, Nobuteru Usuda, Kendo Kiyosawa, Tamie Nakajima^par;, Frank J. Gonzalez^¶ and Toshifumi Aoyama^*

*Department of Aging Biochemistry, Second Department of Internal Medicine, Division of Artificial Kidney, First Department of Anatomy, ^||Department of Hygiene and Medical Genetics, Shinshu University School of Medicine, Matsumoto, Nagano, Japan, ^¶Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland.

Correspondence to Dr. Kazuhiko Hora, Second Department of Internal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan. Phone: +81-263-37-2634; Fax: +81-263-32-9412; E-mail: yujibeat{at}hsp.md.shinshu-u.ac.jp

ABSTRACT. Peroxisome proliferator-activated receptor (PPAR) is a member of the steroid/nuclear receptor superfamily that is intensively expressed in the kidney, but its physiologic function is unknown. In this study, PPAR-null mice were used to help clarify the function. Starved PPAR -null mice were found to secrete significantly more quantities of urine albumin than starved wild-type mice. Furthermore, the appearance of giant lysosomes, marked accumulation of albumin, and an impaired ability concerning albumin digestion were found only in proximal tubules of the starved PPAR-null mice. These abnormalities were probably derived from ATP insufficiency as a result of the starvation-induced decline of carbohydrate metabolism and a lack of PPAR-dependent fatty acid metabolism. It is interesting that these abnormalities disappeared when glucose was administered. Taken together, these findings demonstrate important functions of PPAR in the proximal tubules, the dynamic regulation of the protein-degradation system through maintenance of ATP homeostasis, and emphasize the importance of the fatty acid metabolism in renal physiology.

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