Author:
Ferdaus Mohammed Zubaerul,Terker Andrew Scott,Koumangoye Rainelli,Delpire Eric
Abstract
Loss-of-function mutations in the human potassium chloride cotransporter-3 (KCC3) cause a hereditary motor sensory neuropathy associated with agenesis of the corpus callosum. While recapitulating the neuropathy, KCC3-knockout mice also exhibit high blood pressure. This phenotype is believed to have neurogenic and/or vascular origins. The role of KCC3 in the kidney is poorly understood. KCC3 is encoded by two major isoforms originating from alternative promoters: KCC3a and KCC3b, with KCC3b being the predominant transcript in the kidney. Although the transporter has previously been localized to the proximal tubule, we show here the unique expression of the KCC3a isoform in the connecting tubule. Using a KCC3a-specific polyclonal antibody validated for both immunofluorescence and immunoblotting, we showed an intense KCC3a signal restricted to cortical intercalated cells. No overlap is detected between KCC3a and sodium chloride cotransporter (NCC), a distal convoluted tubule (DCT) marker; or between KCC3a and ENaC or calbindin, which are both principal cell markers. KCC3a signal was observed in cells expressing the apical V-ATPase and pendrin, establishing a unique expression pattern characteristic of intercalated cells of type-B or type-nonA/nonB. We further show that treatment of wild-type mice with hydrochlorothiazide, amiloride, or fed a K+-deficient diet up-regulates KCC3a level, suggesting that volume depletion increases KCC3a abundance. This hypothesis was confirmed by showing a higher abundance of KCC3a protein after 23-h water restriction or after placing the mice on a low-salt diet. More importantly, abundance of the Cl−/HCO3− exchanger, pendrin, which is known to secrete bicarbonate in alkalotic conditions, was significantly diminished in KCC3-knockout mice. In addition, KCC3a abundance increased significantly alongside pendrin abundance in bicarbonate-treated alkalotic mice, providing a credible mechanism for K+ loss in metabolic alkalosis.
Funder
National Institute of Diabetes and Digestive and Kidney Diseases
Fondation Leducq
Subject
Cell Biology,Developmental Biology
Reference59 articles.
1. Hypertension in K-Cl Cotransporter-3 Knockout Mice;Adragna;Adv. Exp. Med. Biol.,2004
2. Rapid Development of Vasopressin Resistance in Dietary K+ Deficiency;Al-Qusairi;Am. J. Physiology-Renal Physiology,2021
3. Genetic Studies of the Andermann Syndrome;Andermann,1994
4. Familial Agenesis of the Corpus Callosum with Anterior Horn Cell Disease: a Syndrome of Mental Retardation, Areflexia and Paraparesis;Andermann;Trans. Am. Neurol. Assoc.,1972
5. Disorders of Sodium and Water Balance in Hospitalized Patients;Bagshaw;Can. J. Anesth/J Can. Anesth.,2009
Cited by
9 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献