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Activation of a Novel Adaptive Mechanism Limits Renal Salt Wasting During Thiazide Inhibition of the Sodium Chloride Cotransporter (NCC)
Author(s) -
Grimm P,
Wall Susan,
Delpire Eric,
Welling Paul
Publication year - 2015
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.29.1_supplement.666.25
Subject(s) - reabsorption , chemistry , renal sodium reabsorption , cotransporter , renal physiology , distal convoluted tubule , homeostasis , endocrinology , nephron , paracrine signalling , medicine , thiazide , sodium , microbiology and biotechnology , biochemistry , biology , renal function , diuretic , receptor , organic chemistry
NCC reabsorbs approximately 10% of filtered NaCl, an amount vital for maintaining extracellular electrolyte and fluid homeostasis. Thiazide inhibition of NCC is used clinically to reduce extracellular fluid volume in treatment of hypertension, but the drugs efficacy often wanes along with its natriuretic properties suggesting activation of another NaCl reabsorptive pathway. Here, we describe an adaptive process in mice given thiazides. Transcriptional profiling, together with protein abundance analysis, reveals an intercalated cell pathway synergizes with a α‐ketoglutarate (αKG) paracrine signaling system to augment sodium chloride reabsorption in distal nephron. Coordinate transcriptional activation of a multi‐gene transport system in pendrin positive intercalated cells (PPIC), involving solute carriers ( Slc26a;Slc4a8 ; Slc4a9) , carbonic anhydrase 2 & 15, and V‐type H + ‐ATPase, collectively form an electroneutral NaCl reabsorption pathway. In the proximal tubule, transcript for glutamine ( Slc6a19 , Slc38a2 , Slc38 a3 ), glutamate ( Slc7a13 ) and α‐KG carriers ( Slc22a13, Slc13a2, Slc13a3, Slc22a6 ) increase, along with the enzymes ( Gls & Glud1 ) responsible for αKG synthesis from these amino acids. Consequently, aKG in tubular fluid is elevated, as is the abundance of its GPCR ( Oxgr1 ), which is expressed on the apical surface of PPIC, allowing paracrine delivery of αKG to stimulate the transport pathway. Identification of the integrated compensatory NaCl reabsorption mechanism provides new molecular targets for diuretics and highlights a potential cause of thiazide resistance.