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Macula densa cells detect altered tissue metabolism via succinate and GPR91
Author(s) -
Vargas Sarah Laurin,
Toma Ildiko,
Kang Jung Julie,
Hanner Fiona,
PetiPeterdi Janos
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.761.17
Subject(s) - macula densa , chemistry , renin–angiotensin system , receptor , medicine , endocrinology , microbiology and biotechnology , biology , biochemistry , blood pressure
Cells of the macula densa (MD) can sense changes in tubular fluid composition and regulate glomerular filtration rate and renin release from the juxtaglomerular apparatus (JGA). MD control of renin release and renin‐angiotensin system (RAS) activation involve MD p38, ERK1/2, COX‐2, synthesis and release of PGE2 acting on JG cells. Diabetes mellitus (DM) is characterized by MD p38 and RAS activation. We hypothesized that MD cells sense a tubular metabolic factor in DM which directly triggers renin release. Using RT‐PCR and immunohistochemistry (IHC), GPR91, a novel metabolic receptor activated by the Krebs‐cycle intermediate succinate, was detected in the mouse MD cell line MMDD1and at the apical plasma membrane of MD cells. Succinate caused a rapid activation of p38and ERK1/2 in MMDD1 cells within 7.5 min detected by immunoblot, which was abolished by GPR91 siRNA. Renal cortical pp38 and renin content increased 2‐fold in STZ‐DM GPR91+/+, but not in GPR91−/− mice. IHC also confirmed the abundance of COX‐2 in the MD in STZ‐DM which was absent in GPR91−/− mice. Confocal microscopy utilizing a PGE2 biosensor technique detected succinate‐induced PGE2 release from MMDD1 cells. In summary, the metabolic receptor GPR91 is expressed in the MD apical membrane and activates p38 and ERK1/2. MD GPR91 activation, most likely through succinate accumulation in the tubular fluid is involved in renin signaling and RAS activation in early DM.