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Author Notes:

Address correspondence to: Paul A. Welling, University of Maryland School of Medicine, Department of Physiology, Bressler Research Building 5-029, 655 West Baltimore Street, Baltimore, Maryland 21201, USA. Phone: 410.706.3851; E-mail: pwelling@umaryland.edu.

The authors have declared that no conflict of interest exists.

Subjects:

Research Funding:

This work was supported by grants from the NIH (DK63049, DK54231, and DK093501, to P.A. Welling; DK32839, to J.B. Wade; GM074771 and DK093501, to E. Delpire; P30NR014129, to S.G. Dorsey; DK55881, to E.J. Weinman; 5T32HL072751, to P.R. Grimm; DK46493, to S.M. Wall; and T32DK07656, to Y. Lazo-Fernandez) and the Research Service, Department of Veterans Affairs (to E.J. Weinman).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • NA+-CL-COTRANSPORTER
  • SODIUM-CHLORIDE COTRANSPORTER
  • SALT-SENSITIVE HYPERTENSION
  • ORGANIC ANION TRANSPORTERS
  • CORTICAL COLLECTING DUCTS
  • BLOOD-PRESSURE REGULATION
  • DISTAL CONVOLUTED TUBULE
  • RENAL INTERCALATED CELLS
  • AMINO-ACID TRANSPORTER
  • ANGIOTENSIN-II
  • Nephrology

Integrated compensatory network is activated in the absence of NCC phosphorylation

Tools:

Journal Title:

Journal of Clinical Investigation

Volume:

Volume 125, Number 5

Publisher:

, Pages 2136-2150

Type of Work:

Article | Final Publisher PDF

Abstract:

Thiazide diuretics are used to treat hypertension; however, compensatory processes in the kidney can limit antihypertensive responses to this class of drugs. Here, we evaluated compensatory pathways in SPAK kinase-deficient mice, which are unable to activate the thiazide-sensitive sodium chloride cotransporter NCC (encoded by Slc12a3). Global transcriptional profiling, combined with biochemical, cell biological, and physiological phenotyping, identified the gene expression signature of the response and revealed how it establishes an adaptive physiology. Salt reabsorption pathways were created by the coordinate induction of a multigene transport system, involving solute carriers (encoded by Slc26a4, Slc4a8, and Slc4a9), carbonic anhydrase isoforms, and V-type H⁺-ATPase subunits in pendrin-positive intercalated cells (PP-ICs) and ENaC subunits in principal cells (PCs). A distal nephron remodeling process and induction of jagged 1/NOTCH signaling, which expands the cortical connecting tubule with PCs and replaces acid-secreting α-ICs with PP-ICs, were partly responsible for the compensation. Salt reabsorption was also activated by induction of an α-ketoglutarate (α-KG) paracrine signaling system. Coordinate regulation of a multigene α-KG synthesis and transport pathway resulted in α-KG secretion into pro-urine, as the α-KG-activated GPCR (Oxgr1) increased on the PP-IC apical surface, allowing paracrine delivery of α-KG to stimulate salt transport. Identification of the integrated compensatory NaCl reabsorption mechanisms provides insight into thiazide diuretic efficacy.

Copyright information:

© 2015, American Society for Clinical Investigation

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