Increased renal renin content in mice lacking the Na+/H+ exchanger NHE2.
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 approximately 2.5-fold using renin immunohistochemistry. Western blotting confirmed approximately 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-PGE(2)-renin release pathway.
Hanner
Fiona
F
Department of Physiology, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California 90033, USA.
Chambrey
Régine
R
Bourgeois
Soline
S
Meer
Elliott
E
Mucsi
István
I
Rosivall
László
L
Shull
Gary E
GE
Lorenz
John N
JN
Eladari
Dominique
D
Peti-Peterdi
János
J
D000818:Animals; D015153:Blotting, Western; D051546:Cyclooxygenase 2 / Q000378:metabolism; D017931:DNA Primers; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D007672:Kidney Cortex / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D012083:Renin / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics*; D013874:Thiopental / Q000031:analogs & derivatives / Q000494:pharmacology
D017931:DNA Primers; C513111:Slc9a2 protein, mouse; D017923:Sodium-Hydrogen Exchangers; C004316:thiobutabarbital; D051546:Cyclooxygenase 2; D012083:Renin; D013874:Thiopental