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High Salt Intake Increases Uroguanylin Expression in Mouse Kidney¹

Institute of Pharmacology and Toxicology (R.P., M.K.) and Department of Internal Medicine, Experimental Nephrology, Westfaelische Wilhelms-Universitaet Muenster, Muenster 48129, Germany; Institute of Cell Biology (E.E.), ETH Hoenggerberg, Zuerich 8093, Switzerland; and Division of Pediatric Endocrinology (L.A.S.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2579

Address all correspondence and requests for reprints to: Dr. Michaela Kuhn, Department of Pharmacology and Toxicology, Westfaelische Wilhelms-Universitaet Muenster, Domagkstrasse 12, D-48129 Muenster, Germany. E-mail: mkuhn{at}uni-muenster.de

The intestinal peptides, guanylin and uroguanylin, may have an important role in the endocrine control of renal function. Both peptides and their receptor, guanylyl cyclase C (GC-C), are also expressed within the kidney, suggesting that they may act locally in an autocrine/paracrine fashion. However, their physiological regulation within the kidney has not been studied. To begin to address this issue, we evaluated the distribution of uroguanylin and guanylin messenger RNA (mRNA) in the mouse nephron and the regulation of renal expression by changes in dietary salt/water intake. Expression was determined in 1) wild-type mice, 2) two strains of receptor-guanylyl cyclase-deficient mice (ANP-receptor-deficient, GC-A-/-, and GC-C-deficient mice); and 3) cultured renal epithelial (M-1) cells, by RT-PCR, Northern blotting and immunocytochemistry.

Renal uroguanylin messenger RNA expression was higher than guanylin and had a different distribution pattern, with highest levels in the proximal tubules, whereas guanylin was mainly expressed in the collecting ducts. Uroguanylin expression was significantly lower in GC-C-/- mice than in GC-A-/- and wild-types, suggesting that absence of a receptor was able to down-regulate ligand expression. Salt-loading (1% NaCl in drinking water) increased uroguanylin-mRNA expression by >1.8-fold but had no effect on guanylin expression. Uroguanylin but not guanylin transcripts were detected in M-1 cells and increased in response to hypertonic media (+NaCl or mannitol). Our results indicate that high-salt intake increases uroguanylin but not guanylin expression in the mouse kidney. The synthesis of these peptides by tubular epithelium may contribute to the local control of renal function and its adaptation to dietary salt.

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