Abstract
Mutations in the SLC4A1 gene encoding the anion exchanger 1 (AE1) can cause distal renal tubular acidosis (dRTA), a disease often due to mis-trafficking of the mutant protein. In this study, we investigated whether trafficking of a Golgi-retained dRTA mutant, G701D kAE1, or two dRTA mutants retained in the endoplasmic reticulum, C479W and R589H kAE1, could be functionally rescued to the plasma membrane of Madin-Darby Canine Kidney (MDCK) cells. Treatments with DMSO, glycerol, the corrector VX-809, or low temperature incubations restored the basolateral trafficking of G701D kAE1 mutant. These treatments had no significant rescuing effect on trafficking of the mis-folded C479W or R589H kAE1 mutants. DMSO was the only treatment that partially restored G701D kAE1 function in the plasma membrane of MDCK cells. Our experiments show that trafficking of intracellularly retained dRTA kAE1 mutants can be partially restored, and that one chemical treatment rescued both trafficking and function of a dRTA mutant. These studies provide an opportunity to develop alternative therapeutic solutions for dRTA patients.
Highlights
Distal renal tubular acidosis is a dominantly or recessively inherited disease characterized by development of metabolic acidosis, inability to acidify urine, hypokalemia, nephrocalcinosis, and eventually renal failure if untreated [1]
We examined whether the trafficking of one dominant (R589H) and two recessive (C479W and G701D) Distal renal tubular acidosis (dRTA) mutants of kAE1 could be restored to the plasma membrane by treating cells with DMSO, glycerol, low temperature incubations or the pharmacological chaperone VX-809
We studied the trafficking of WT and mutant kAE1 carrying an extracellular hemaglutinin epitope when expressed in Madin-Darby Canine Kidney (MDCK) cells
Summary
Distal renal tubular acidosis (dRTA) is a dominantly or recessively inherited disease characterized by development of metabolic acidosis, inability to acidify urine, hypokalemia, nephrocalcinosis, and eventually renal failure if untreated [1]. Mutations in the SLC4A1 gene encoding anion exchanger 1 (AE1) can cause dRTA, often due to altered trafficking of the mutant protein [2]. AE1 is expressed in red blood cells (eAE1) where it plays a crucial role in respiration. Up to 16 mutations in the SLC4A1 gene have been identified that cause dRTA [3,4,5,6]. It is possible that cell-specific chaperones expressed either in red blood cells, such as glycophorin A (GPA) [7], or kidney cells promote proper folding of dRTA or HS mutants, respectively. Stringency of the qualitycontrol machineries may differ between kidneys and red blood cells, resulting in differential surface expression of AE1 mutants depending on the cell type. Recent advances showed that dominant dRTA mutants retain wild-type (WT) kAE1 intracellularly, while recessive dRTA mutants have their trafficking rescued by co-expression with WT kAE1 [8]
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