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Increased renal renin content in mice lacking the Na⁺/H⁺ exchanger NHE2

Departments of ¹Physiology and Biophysics and Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California; ²Institut National de la Santé et de la Recherche Médicale Unité 872, Centre de Recherche des Cordeliers and Faculté de Medecine René Descartes, Université Paris V, Paris; ³Hungarian Academy of Sciences, Semmelweis University Research Group for Pediatrics and Nephrology, and ⁴1st Department of Medicine and ⁵Institute of Pathophysiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary; ⁶Departments of Molecular Genetics, Biochemistry, and Microbiology and ⁷Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio; and ⁸Département de Physiologie, Hôpital Necker-Enfants Malades, Paris, France

Submitted 12 December 2007 ; accepted in final form 19 February 2008

Macula densa (MD) cells express the Na⁺/H⁺ exchanger (NHE) isoform NHE2 at the apical membrane, which may play an important role in tubular salt sensing through the regulation of cell volume and intracellular pH. These studies aimed to determine whether NHE2 participates in the MD control of renin synthesis. Renal renin content and activity and elements of the MD signaling pathway were analyzed using wild-type (NHE2^+/+) and NHE2 knockout (NHE2^–/–) mice. Immunofluorescence studies indicated that NHE2^–/– mice lack NHE3 at the MD apical membrane, so the other apical NHE isoform has not compensated for the lack of NHE2. Importantly, the number of renin-expressing cells in the afferent arteriole in NHE2^–/– mice was increased 2.5-fold using renin immunohistochemistry. Western blotting confirmed 20% higher renal cortical renin content in NHE2^–/– mice compared with wild type. No-salt diet for 1 wk significantly increased renin content and activity in NHE2^+/+ mice, but the response was blunted in NHE2^–/– mice. Renal tissue renin activity and plasma renin concentration were elevated three- and twofold, respectively, in NHE2^–/– mice compared with wild type. NHE2^–/– mice also exhibited a significantly increased renal cortical cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase (mPGES) expression, indicating MD-specific mechanisms responsible for the increased renin content. Significant and chronic activation of ERK1/2 was observed in MD cells of NHE2^–/– kidneys. Removal of salt or addition of NHE inhibitors to cultured mouse MD-derived (MMDD1) cells caused a time-dependent activation of ERK1/2. In conclusion, the NHE2 isoform appears to be important in the MD feedback control of renin secretion, and the signaling pathway likely involves MD cell shrinkage and activation of ERK1/2, COX-2, and mPGES, all well-established elements of the MD-PGE₂-renin release pathway.

macula densa; cell volume; renin release; mitogen-activated protein kinases; cyclooxygenase-2

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