NBC1 and Proximal RTA: Pathogenesis and Treatment

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DESCRIPTION (provided by applicant): Renal tubular acidosis is an important cause of metabolic acidosis in patients. In patients with proximal renal tubular acidosis (RTA), the severity of the metabolic acidosis tends to be greater than patients with distal RTA. Metabolic acidosis can affect important biochemical pathways and perturb the function of various organ systems. Patients with renal tubular acidosis often have extrarenal manifestations that cannot be treated effectively with base therapy. Unfortunately, we currently lack specific treatments that target the underlying transport abnormalities in the proximal tubule and in extrarenal tissues. Recent advances in our understanding of the underlying transport defects in patients with genetic forms of RTA offer a unique opportunity to devise specific therapeutic approaches that target specific transporter mutations. The focus of this proposal is on the molecular pathogenesis and treatment of autosomal recessive proximal RTA. Hereditary proximal renal tubular acidosis results from mutations in the SLC4A4 electrogenic sodium bicarbonate cotransporter NBC1. NBC1 is responsible for mediating basolateral bicarbonate absorption in the proximal tubule and bicarbonate transport in extrarenal tissues including the pancreas, eye, and brain. Mutations in the NBC1 transporter presents a therapeutic challenge given the known missense, nonsense, and deletion mutations that decrease cotransporter function in this disorder. In preliminary experiments, we have begun to fill the current gap in our understanding of the biosynthesis, structural properties, organelle trafficking, and functional abnormalities of mutant cotransporters, with the goal of devising targeted therapeutic strategies for specific classes of NBC1 mutations. Our experiments have utilized mammalian HEK-293 and mPCT expression systems to address the aims of this proposal. The novelty of this proposal is that new therapeutic modalities have been found in preliminary studies that can potentially target specific NBC1 mutations causing proximal RTA. The data obtained from the results of this proposal could provide an important basis for future therapy of this disease in humans. The experiments in this proposal will confirm our preliminary findings, define the physiologic and molecular mechanisms underlying novel approaches for treating specific NBC1 mutations, and potentially play a role in therapeutic trials in animal models and ultimately patients with proximal renal tubular acidosis.