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Accession IconGSE60728

Differential gene expression in renal cortex resulting from SPAK gene disruption

Organism Icon Mus musculus
Sample Icon 8 Downloadable Samples
Technology Badge Icon Affymetrix Mouse Gene 1.0 ST Array (mogene10st)

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Poorly defined adaptive processes maintain salt balance when the renal thiazide-sensitive sodium-chloride cotransporter is inhibited, limiting diuretic efficacy. Here, we identify underlying mechanisms in SPAK kinase null mice, which are unable to phospho-activate NCC. Global transcriptional profiling, combined with biochemical, cell biological and physiological phenotyping, identified the gene expression signature of the response, and revealed how it establishes a new adaptive physiology. Salt reabsorption pathways are created by the coordinate induction of a multi-gene transport system, involving solute carriers (Slc26a; Slc4a8; Slc4a9), carbonic anhydrase isoforms, and V-type H+-ATPase subunits in pendrin-positive intercalated cells (PP-IC), and ENaC subunits in principal cells. A distal nephron remodeling process and induction of Jagged 1-Notch signaling, which expands the cortical connecting tubule with principal cells and replaces acid-secreting - intercalated cells with PP-IC, is partly responsible. Salt reabsorption is also activated by induction of an alpha-ketoglutarate (-KG) paracrine signaling system. Coordinate regulation of a multigene -KG synthesis and transport pathway cause -KG to be secreted into the pro-urine as the -KG activated GPCR (Oxgr1) increases on the PP-IC apical surface, allowing paracrine delivery of -KG to stimulate salt transport. Identification of the integrated compensatory NaCl reabsorption mechanisms provides new insights into thiazide diuretic efficacy.
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