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 multige...Continue Reading
Differentiation of renal beta-intercalated cells to alpha-intercalated and principal cells in culture
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Dietary Cl(-) restriction upregulates pendrin expression within the apical plasma membrane of type B intercalated cells
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Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule
Molecular pathogenesis of pseudohypoaldosteronism type II: generation and analysis of a Wnk4(D561A/+) knockin mouse model
Reduced ENaC protein abundance contributes to the lower blood pressure observed in pendrin-null mice
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Activation of the thiazide-sensitive Na+-Cl- cotransporter by the WNK-regulated kinases SPAK and OSR1
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Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone
From the Cover: Whole-genome association study identifies STK39 as a hypertension susceptibility gene
Potassium restriction, high protein intake, and metabolic acidosis increase expression of the glutamine transporter SNAT3 (Slc38a3) in mouse kidney
The thiazide-sensitive Na+-Cl- cotransporter: molecular biology, functional properties, and regulation by WNKs
Expression and phosphorylation of the Na+-Cl- cotransporter NCC in vivo is regulated by dietary salt, potassium, and SGK1
Inactivation of Notch signaling in the renal collecting duct causes nephrogenic diabetes insipidus in mice
The Na+-dependent chloride-bicarbonate exchanger SLC4A8 mediates an electroneutral Na+ reabsorption process in the renal cortical collecting ducts of mice
Angiotensin II induces phosphorylation of the thiazide-sensitive sodium chloride cotransporter independent of aldosterone
Claudin-4 forms paracellular chloride channel in the kidney and requires claudin-8 for tight junction localization
Deletion of hensin/DMBT1 blocks conversion of beta- to alpha-intercalated cells and induces distal renal tubular acidosis
Differential interaction of dicarboxylates with human sodium-dicarboxylate cotransporter 3 and organic anion transporters 1 and 3
Double knockout of pendrin and Na-Cl cotransporter (NCC) causes severe salt wasting, volume depletion, and renal failure
Genomic association analysis of common variants influencing antihypertensive response to hydrochlorothiazide
Evaluation of cellular plasticity in the collecting duct during recovery from lithium-induced nephrogenic diabetes insipidus
Electroneutral absorption of NaCl by the aldosterone-sensitive distal nephron: implication for normal electrolytes homeostasis and blood pressure regulation
Sympathetic stimulation of thiazide-sensitive sodium chloride cotransport in the generation of salt-sensitive hypertension
Effects of acid challenges on type 2 angiotensin II receptor-sensitive ammonia production by the proximal tubule
Double Knockout of the Na+-Driven Cl-/HCO3- Exchanger and Na+/Cl- Cotransporter Induces Hypokalemia and Volume Depletion
SPAK and OSR1 play essential roles in potassium homeostasis through actions on the distal convoluted tubule
Unsung renal receptors: orphan G-protein-coupled receptors play essential roles in renal development and homeostasis
Expression of sodium-dependent dicarboxylate transporter 1 (NaDC1/SLC13A2) in normal and neoplastic human kidney
New insights into sodium transport regulation in the distal nephron: Role of G-protein coupled receptors
α-Ketoglutarate stimulates pendrin-dependent Cl- absorption in the mouse CCD through protein kinase C
Consequences of SPAK inactivation on Hyperkalemic Hypertension caused by WNK1 mutations: evidence for differential roles of WNK1 and WNK4
Renal Tubular Ubiquitin-Protein Ligase NEDD4-2 Is Required for Renal Adaptation during Long-Term Potassium Depletion
Endogenous Notch Signaling in Adult Kidneys Maintains Segment-Specific Epithelial Cell Types of the Distal Tubules and Collecting Ducts to Ensure Water Homeostasis
A role for tubular Na+/H+ exchanger NHE3 in the natriuretic effect of the SGLT2 inhibitor empagliflozin.
WNK-SPAK/OSR1-NCC kinase signaling pathway as a novel target for the treatment of salt-sensitive hypertension.
A Randomized Trial of Distal Diuretics versus Dietary Sodium Restriction for Hypertension in Chronic Kidney Disease.
α-Ketoglutarate drives electroneutral NaCl reabsorption in intercalated cells by activating a G-protein coupled receptor, Oxgr1
In human nephrectomy specimens, the kidney level of tubular transport proteins does not correlate with their abundance in urinary extracellular vesicles
Potassium depletion induces cellular conversion in the outer medullary collecting duct altering Notch signaling pathway.
The Cl- /HCO3- exchanger pendrin is downregulated during oral co-administration of exogenous mineralocorticoid and KCl in patients with primary aldosteronism
Mechanisms coupling sodium and magnesium reabsorption in the distal convoluted tubule of the kidney.
Foxi1 inactivation rescues loss of principal cell fate selection in Hes1-deficient kidneys but does not ensure maintenance of principal cell gene expression.
Antihypertensive Agents: Mechanisms of Action
Antihypertensive drugs are used to treat hypertension (high blood pressure) which aims to prevent the complications of high blood pressure, such as stroke and myocardial infarction. Discover the latest research on antihypertensive drugs and their mechanism of action here.