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Evidence Indicating that Renal Tubular Metabolism of Leptin Is Mediated by Megalin But Not by the Leptin Receptors

Division of Clinical Nephrology and Rheumatology (H.H., A.S., T.T., A.T., Y.X., K.S., J.J.K., F.G.) and Department of Applied Molecular Medicine (A.S., T.T.), Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan; and Division of Intensive Care Medicine (J.J.K.), Niigata University Medical Hospital, Niigata 951-8510, Japan

Address all correspondence and requests for reprints to: Akihiko Saito, M.D., Ph.D., Department of Applied Molecular Medicine, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Niigata 951-8510, Japan. E-mail: akisaito{at}med.niigata-u.ac.jp.

Leptin is secreted by adipocytes and is a circulating factor that regulates food intake and energy expenditure. Its serum level is elevated in patients with renal failure and has been suggested to be associated with malnutritional factors in these patients. Leptin has been suggested to be primarily metabolized by the kidneys, although the precise molecular mechanisms are not known. The purpose of this study was to determine the nephron segments and potential receptors involved in renal leptin metabolism. To determine the segment involved in leptin uptake, we performed histoautoradiography of kidney sections obtained from rats that had been injected iv with ¹²⁵I-leptin. The ability of megalin, a multiligand endocytic receptor in the proximal tubules, to bind and endocytose leptin was examined by ligand blotting analysis, quartz-crystal microbalance, and degradation assays using megalin-expressing rat yolk sac L2 cells. Immunohistochemistry was performed to localize leptin receptors (LEP-R) in the rat kidney using two antibodies that recognize different epitopes on the LEP-R proteins. Circulating ¹²⁵I-leptin was filtered by glomeruli and internalized by proximal convoluted tubules. Megalin bound leptin in the presence of Ca²⁺ and mediated its cellular internalization and degradation. On immunohistochemistry, LEP-R were localized in the proximal straight tubules, loops of Henle, distal tubules, and collecting ducts. In conclusion, circulating leptin was filtered by glomeruli and taken up by proximal convoluted tubules, where megalin likely mediates its binding and uptake. The localization of LEP-R suggests that they are not primarily involved in leptin metabolism in the proximal tubules.

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