A role for Rhesus factor Rhcg in renal ammonium excretion and male fertility

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Abstract

The kidney has an important role in the regulation of acid–base homeostasis. Renal ammonium production and excretion are essential for net acid excretion under basal conditions and during metabolic acidosis. Ammonium is secreted into the urine by the collecting duct, a distal nephron segment where ammonium transport is believed to occur by non-ionic NH3 diffusion coupled to H+ secretion. Here we show that this process is largely dependent on the Rhesus factor Rhcg. Mice lacking Rhcg have abnormal urinary acidification due to impaired ammonium excretion on acid loading—a feature of distal renal tubular acidosis. In vitro microperfused collecting ducts of Rhcg-/- acid-loaded mice show reduced apical permeability to NH3 and impaired transepithelial NH3 transport. Furthermore, Rhcg is localized in epididymal epithelial cells and is required for normal fertility and epididymal fluid pH. We anticipate a critical role for Rhcg in ammonium handling and pH homeostasis both in the kidney and the male reproductive tract.

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Figure 1: Gene targeting of Rhcg.
Figure 2: Impaired acid-stress handling in Rhcg -/- mice.
Figure 3: Reduced NH 3 permeability of microperfused collecting ducts segments from Rhcg -/- acid-challenged mice.
Figure 4: Rhcg in the male genital tract.

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Acknowledgements

We are grateful to P. Drèze, B. André and P. Gabant for their contribution to the initial step of this study. We thank H. Mezdour, L. Pouilly and P. Persoons for microinjection experiments, B. Pajak for help in broad-spectrum histological assessment, V. Beaujean, Y. Cnops, H. Debaix and T. Nishino for excellent technical assistance, and A. Tamah and M.-F. Vincent for amino acid chromatography. These studies were supported by the Belgian agencies FNRS and FRSM (3.4.546.04.F, 3.4.635.05.F, 3.4592.06.F), the ‘Fonds Brachet-recherche’, the ‘Fonds Van Buuren’, the ‘Fondation Alphonse & Jean Forton’, a Concerted Research Action (05/10-328), an Inter-university Attraction Pole (IUAP P6/05), the Swiss National Science Foundation (31-109677), an INSERM grant, and the EuReGene and EUNEFRON (GA#201590) projects of the European Community (FP6 and FP7). S.Bi. was the recipient of a FRIA fellowship; H.B., A.M.M. and C.S. are Research fellow, Research associate and Research director of the FNRS, respectively.

Author Contributions S.Bi., J.S., C.S. and A.M.M. developed the concept of this study; all authors contributed to the intellectual design, execution and interpretation of the experiments; S.Bi. and A.M.M. wrote the paper with specific contribution of all authors and the particular involvement of O.D. and C.A.W. All authors analysed and discussed the data, and commented on the final version of the manuscript. S.Bi., H.B. and S.Bo. share first authorship.

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Correspondence to Anna Maria Marini.

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Biver, S., Belge, H., Bourgeois, S. et al. A role for Rhesus factor Rhcg in renal ammonium excretion and male fertility. Nature 456, 339–343 (2008) doi:10.1038/nature07518

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