Intracellular chloride

Abstract

Purpose of review-This review focuses on the role of intracellular chloride in regulating transepithelial ion transport in the distal convoluted tubule (DCT) in response to perturbations in plasma homeostasis. Recent findings-Low dietary potassium increases the phosphorylation and activity of the sodium chloride cotransporter (NCC) in the DCT, and vice versa, affecting sodium-dependent potassium secretion in the downstream aldosterone-sensitive distal nephron. In cells, NCC phosphorylation is increased by lowering of intracellular chloride, via activation of the chloridesensitive WNK (With No Lysine)-SPAK/OSR1 (Ste20-related proline/alanine rich kinase/ oxidative stress response) kinase cascade. In vivo studies have demonstrated pathway activation in the kidney in response to low dietary potassium. A possible mechanism is lowering of DCT intracellular chloride in response to low potassium due to parallel basolateral potassium and chloride channels. Recent studies support a role for these channels in the response of NCC to varying potassium. Studies examining chloride-insensitive WNK mutants, in the Drosophila renal tubule and in the mouse, lend further support to a role for chloride in regulating WNK activity and transepithelial ion transport. Caveats, alternatives and future directions are also discussed. Summary-Chloride sensing by WNK kinase provides a mechanism to allow coupling of extracellular potassium with NCC phosphorylation and activity to maintain potassium homeostasis.

Differential effects of sodium chloride and monosodium glutamate on kidney of adult and aging mice

“…Lastly, sodium chloride ingestion implies that both sodium and chloride ions may act inside the body: indeed, hyperchloremia is associated to renal vasoconstriction that decreases the glomerular filtration rate, due to the autoregulatory tubule-glomerular feedback control mechanism 58 . Moreover, chloride is a modulator of transtubular transport via the sodium chloride cotransporter, functionally coupled to potassium flux 59 . Extracellular chloride may also activate a molecular switch on collagen IV which promotes scaffolding outside the cells, thus impairing kidney tissue architecture and ultimately its function 60 .…”

Consideration of Kinase Inhibitors for the Treatment of Hydrocephalus

“…The WNK family of kinases are bona fide Cl − sensors within the physiological range. Cl − binding inhibits autophosphorylation and activation [ 95 , 96 , 97 , 98 ]. Cl − secretion and the resulting decrease in intracellular concentration could lead to the activation of WNK, followed by the phosphorylation and activation of SPAK/OSR1 and, subsequently, NKCC1.…”

Roles of Sodium-Glucose Cotransporter 2 of Mesangial Cells in Diabetic Kidney Disease

“…Moreover, tubule-interstitial fibrosis is also considered as a characteristic pathological change of the early stage of DN [ 67 ]. Renal interstitial cells always function as exchangers of various ions or reabsorbs of various ions and substances, such as glucose [ 41 , 68 , 69 ]. Under diabetic conditions, however, these cells are exposed to hypoxia and the activated HIF-1 leads to fibrosis [ 70-72 ].…”