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The Physiological Effect of Altering Mitochondrial Calcium Uptake in the Renal Cortical Collecting Duct
Author(s) -
GalarzaPaez Laura I,
Eaton Douglas C,
Zou Li,
AlKhalili Otor,
Ma Heping,
Sands Jeff M,
Klein Janet D,
Thai Tiffany L
Publication year - 2016
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.30.1_supplement.1224.13
Subject(s) - mitochondrion , reabsorption , chemistry , microbiology and biotechnology , epithelial polarity , calcium , extracellular , apical membrane , renal cortex , calcium signaling , kidney , intracellular , medicine , endocrinology , biochemistry , biology , cell , membrane , organic chemistry
Principal cells in the renal collecting duct (CCD) regulate total body salt and water. The principal cells respond differently to extracellular signals depending upon whether the signals are delivered to the apical or basolateral surface of the cells. Specifically, basolateral ATP increases epithelial sodium channel (ENaC) activity and transepithelial sodium reabsorption whereas apical ATP is inhibitory. Paradoxically, both of these opposing signaling pathways are mediated by an increase intracellular calcium ([Ca 2+ ] i ). We have shown recently that mitochondria localize beneath the apical and basolateral plasma membranes in principal cells to reduce the rate of [Ca 2+ ] i diffusion away from the poles of the cell and, thereby, allow elevated [Ca 2+ ]i within specific regions of the cell. Ca 2+ uptake into mitochondria is a two‐step process, occurring via the voltage dependent anion channel (VDAC) in the outer mitochondrial membrane, a channel which can transport anions or cations depending on conformation, and then through the mitochondrial calcium uniporter in the mitochondrial inner membrane. After Ca 2+ is rapidly sequestered by the mitochondria, it is only slowly released, promoting [Ca 2+ ]i buffering. We asked whether genetically inducing a deficiency in mitochondrial Ca 2+ uptake that would prevent the development of locally high [Ca 2+ ]i would produce a renal or cardiovascular phenotype due to Ca 2+ ‐dependent misregulation of ENaC. We compared blood pressure and kidney morphology in wild type mice and those lacking VDAC3 at baseline and after two weeks of 8% salt diet. At baseline, kidney morphology and blood pressure were similar between the two strains (106.3±4.85 mmHg vs 94.8±3.87 mmHg, P>0.1). After two weeks of high salt diet, VDAC3 KO mice showed glomerular atrophy that was not seen in wild type animals and they had a higher blood pressure than their wild type littermates (127.5mmHg ±6.89 vs 109.0mmHg ±3.77, P<0.05). These data suggest that a genetic defect in mitochondrial Ca 2+ uptake results in the development of renal and cardiovascular damage in response to high salt. Support or Funding Information NIH 5R25DK101390, NIH R37‐DK037963 to DCE, NIH R01‐DK100582 to HM and AHA 13POST16820072 to TLT.