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      Molecular Pathophysiology of Renal Tubular Acidosis

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          Abstract

          Renal tubular acidosis (RTA) is characterized by metabolic acidosis due to renal impaired acid excretion. Hyperchloremic acidosis with normal anion gap and normal or minimally affected glomerular filtration rate defines this disorder. RTA can also present with hypokalemia, medullary nephrocalcinosis and nephrolitiasis, as well as growth retardation and rickets in children, or short stature and osteomalacia in adults. In the past decade, remarkable progress has been made in our understanding of the molecular pathogenesis of RTA and the fundamental molecular physiology of renal tubular transport processes. This review summarizes hereditary diseases caused by mutations in genes encoding transporter or channel proteins operating along the renal tubule. Review of the molecular basis of hereditary tubulopathies reveals various loss-of-function or gain-of-function mutations in genes encoding cotransporter, exchanger, or channel proteins, which are located in the luminal, basolateral, or endosomal membranes of the tubular cell or in paracellular tight junctions. These gene mutations result in a variety of functional defects in transporter/channel proteins, including decreased activity, impaired gating, defective trafficking, impaired endocytosis and degradation, or defective assembly of channel subunits. Further molecular studies of inherited tubular transport disorders may shed more light on the molecular pathophysiology of these diseases and may significantly improve our understanding of the mechanisms underlying renal salt homeostasis, urinary mineral excretion, and blood pressure regulation in health and disease. The identification of the molecular defects in inherited tubulopathies may provide a basis for future design of targeted therapeutic interventions and, possibly, strategies for gene therapy of these complex disorders.

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          Most cited references60

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          Renal tubular acidosis: the clinical entity.

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            Familial distal renal tubular acidosis is associated with mutations in the red cell anion exchanger (Band 3, AE1) gene.

            All affected patients in four families with autosomal dominant familial renal tubular acidosis (dRTA) were heterozygous for mutations in their red cell HCO3-/Cl- exchanger, band 3 (AE1, SLC4A1) genes, and these mutations were not found in any of the nine normal family members studied. The mutation Arg589--> His was present in two families, while Arg589--> Cys and Ser613--> Phe changes were found in the other families. Linkage studies confirmed the co-segregation of the disease with a genetic marker close to AE1. The affected individuals with the Arg589 mutations had reduced red cell sulfate transport and altered glycosylation of the red cell band 3 N-glycan chain. The red cells of individuals with the Ser613--> Phe mutation had markedly increased red cell sulfate transport but almost normal red cell iodide transport. The erythroid and kidney isoforms of the mutant band 3 proteins were expressed in Xenopus oocytes and all showed significant chloride transport activity. We conclude that dominantly inherited dRTA is associated with mutations in band 3; but both the disease and its autosomal dominant inheritance are not related simply to the anion transport activity of the mutant proteins.
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              Carbonic anhydrase II deficiency identified as the primary defect in the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification.

              The clinical, radiological, and pathological findings in three siblings affected with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification have been reported. In an effort to explain the pleiotropic effects of the mutation producing this disorder, we postulated a defect in carbonic anhydrase II (CA II), the only one of the three soluble isozymes of carbonic anhydrase that is known to be synthesized in kidney and brain. We report here biochemical and immunological evidence for the virtual absence of CA II in erythrocytes of patients affected with this condition, whereas CA I level is not reduced. Levels of CA II in erythrocyte hemolysates from asymptomatic obligate heterozygotes are about half of normal. These findings: (i) elucidate the basic defect in one form of inherited osteopetrosis; (ii) provide genetic evidence implicating CA II in osteoclast function and bone resorption; (iii) explain previous observations that carbonic anhydrase inhibitors block the normal parathyroid hormone-induced release of calcium from bone; (iv) clarify the role of renal CA II in urinary acidification and bicarbonate reabsorption; and (v) suggest a method to identify heterozygous carriers for the gene for this recessively inherited syndrome.
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                Author and article information

                Journal
                Curr Genomics
                CG
                Current Genomics
                Bentham Science Publishers Ltd
                1389-2029
                1875-5488
                March 2009
                : 10
                : 1
                : 51-59
                Affiliations
                []Pediatric Nephrology Unit, Department of Pediatrics, School of Medicine – Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
                Author notes
                [* ]Address correspondence to this author at the Rua Engenheiro Amaro Lanari, 389 / apt 501, Belo Horizonte-Minas Gerais, 30310-580, Brazil; Tel: +55-31-99797782; Fax: +55-31-32851056; E-mail: eduolive@ 123456medicina.ufmg.br
                Article
                CG-10-51
                10.2174/138920209787581262
                2699831
                19721811
                e361e340-7a70-49ad-a763-17fb1d6334f6
                ©2009 Bentham Science Publishers Ltd.

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.5/), which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 9 October 2008
                : 8 November 2008
                : 12 November 2008
                Categories
                Article

                Genetics
                tubular transport,renal tubular acidosis,acid-base homeostasis,molecular physiology,gene mutations.

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