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Modulation of brain cation-Cl- cotransport via the SPAK kinase inhibitor ZT-1a.

ABSTRACT: The SLC12A cation-Cl- cotransporters (CCC), including NKCC1 and the KCCs, are important determinants of brain ionic homeostasis. SPAK kinase (STK39) is the CCC master regulator, which stimulates NKCC1 ionic influx and inhibits KCC-mediated efflux via phosphorylation at conserved, shared motifs. Upregulation of SPAK-dependent CCC phosphorylation has been implicated in several neurological diseases. Using a scaffold-hybrid strategy, we develop a novel potent and selective SPAK inhibitor, 5-chloro-N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxybenzamide ("ZT-1a"). ZT-1a inhibits NKCC1 and stimulates KCCs by decreasing their SPAK-dependent phosphorylation. Intracerebroventricular delivery of ZT-1a decreases inflammation-induced CCC phosphorylation in the choroid plexus and reduces cerebrospinal fluid (CSF) hypersecretion in a model of post-hemorrhagic hydrocephalus. Systemically administered ZT-1a reduces ischemia-induced CCC phosphorylation, attenuates cerebral edema, protects against brain damage, and improves outcomes in a model of stroke. These results suggest ZT-1a or related compounds may be effective CCC modulators with therapeutic potential for brain disorders associated with impaired ionic homeostasis.

SUBMITTER: Zhang J

PROVIDER: S-EPMC6946680 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Modulation of brain cation-Cl<sup>-</sup> cotransport via the SPAK kinase inhibitor ZT-1a.

Zhang Jinwei J Bhuiyan Mohammad Iqbal H MIH Zhang Ting T Karimy Jason K JK Wu Zhijuan Z Fiesler Victoria M VM Zhang Jingfang J Huang Huachen H Hasan Md Nabiul MN Skrzypiec Anna E AE Mucha Mariusz M Duran Daniel D Huang Wei W Pawlak Robert R Foley Lesley M LM Hitchens T Kevin TK Minnigh Margaret B MB Poloyac Samuel M SM Alper Seth L SL Molyneaux Bradley J BJ Trevelyan Andrew J AJ Kahle Kristopher T KT Sun Dandan D Deng Xianming X

Nature communications 20200107 1

The SLC12A cation-Cl<sup>-</sup> cotransporters (CCC), including NKCC1 and the KCCs, are important determinants of brain ionic homeostasis. SPAK kinase (STK39) is the CCC master regulator, which stimulates NKCC1 ionic influx and inhibits KCC-mediated efflux via phosphorylation at conserved, shared motifs. Upregulation of SPAK-dependent CCC phosphorylation has been implicated in several neurological diseases. Using a scaffold-hybrid strategy, we develop a novel potent and selective SPAK inhibitor ...[more]

PMID: 31911626

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Project description:BackgroundThe tight junction proteins claudin-2 and claudin-10a form paracellular cation and anion channels, respectively, and are expressed in the proximal tubule. However, the physiologic role of claudin-10a in the kidney has been unclear.MethodsTo investigate the physiologic role of claudin-10a, we generated claudin-10a-deficient mice, confirmed successful knockout by Southern blot, Western blot, and immunofluorescence staining, and analyzed urine and serum of knockout and wild-type animals. We also used electrophysiologic studies to investigate the functionality of isolated proximal tubules, and studied compensatory regulation by pharmacologic intervention, RNA sequencing analysis, Western blot, immunofluorescence staining, and respirometry.ResultsMice deficient in claudin-10a were fertile and without overt phenotypes. On knockout, claudin-10a was replaced by claudin-2 in all proximal tubule segments. Electrophysiology showed conversion from paracellular anion preference to cation preference and a loss of paracellular Cl- over HCO3- preference. As a result, there was tubular retention of calcium and magnesium, higher urine pH, and mild hypermagnesemia. A comparison with other urine and serum parameters under control conditions and sequential pharmacologic transport inhibition, and unchanged fractional lithium excretion, suggested compensative measures in proximal and distal tubular segments. Changes in proximal tubular oxygen handling and differential expression of genes regulating fatty acid metabolism indicated proximal tubular adaptation. Western blot and immunofluorescence revealed alterations in distal tubular transport.ConclusionsClaudin-10a is the major paracellular anion channel in the proximal tubule and its deletion causes calcium and magnesium hyper-reabsorption by claudin-2 redistribution. Transcellular transport in proximal and distal segments and proximal tubular metabolic adaptation compensate for loss of paracellular anion permeability.

Dataset Information

Modulation of brain cation-Cl- cotransport via the SPAK kinase inhibitor ZT-1a.

Publications

Modulation of brain cation-Cl<sup>-</sup> cotransport via the SPAK kinase inhibitor ZT-1a.

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