Integrated compensatory network is activated in the absence of NCC phosphorylation

J Clin Invest. 2015 May;125(5):2136-50. doi: 10.1172/JCI78558. Epub 2015 Apr 20.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amiloride / analogs & derivatives
  • Amiloride / pharmacology
  • Ammonia / metabolism
  • Animals
  • Biological Transport
  • Blood Pressure / physiology*
  • Carbonic Anhydrases / genetics
  • Carbonic Anhydrases / physiology
  • Chlorides / urine*
  • Disease Models, Animal
  • Enzyme Activation
  • Epithelial Sodium Channels / physiology
  • Gene Expression Profiling
  • Gene Regulatory Networks
  • Gitelman Syndrome / genetics
  • Gitelman Syndrome / physiopathology*
  • Ketoglutaric Acids / metabolism
  • Kidney Glomerulus / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Natriuresis / genetics
  • Natriuresis / physiology*
  • Nephrons / metabolism*
  • Paracrine Communication
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptors, Notch / physiology
  • Receptors, Purinergic P2 / physiology
  • Renal Reabsorption / physiology*
  • Signal Transduction
  • Sodium Chloride / pharmacokinetics
  • Sodium-Potassium-Chloride Symporters / genetics
  • Sodium-Potassium-Chloride Symporters / physiology
  • Solute Carrier Family 12, Member 3 / metabolism


  • Chlorides
  • Epithelial Sodium Channels
  • Ketoglutaric Acids
  • OXGR1 protein, mouse
  • Receptors, Notch
  • Receptors, Purinergic P2
  • Slc12a3 protein, mouse
  • Sodium-Potassium-Chloride Symporters
  • Solute Carrier Family 12, Member 3
  • benzamil
  • Sodium Chloride
  • Ammonia
  • Amiloride
  • Stk39 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Carbonic Anhydrases