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      Recent advances in understanding ion transport mechanisms in polycystic kidney disease

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          Abstract

          This review focuses on the most recent advances in the understanding of the electrolyte transport-related mechanisms important for the development of severe inherited renal disorders, autosomal dominant (AD) and recessive (AR) forms of polycystic kidney disease (PKD). We provide here a basic overview of the origins and clinical aspects of ARPKD and ADPKD and discuss the implications of electrolyte transport in cystogenesis. Special attention is devoted to intracellular calcium handling by the cystic cells, with a focus on polycystins and fibrocystin, as well as other calcium level regulators, such as transient receptor potential vanilloid type 4 (TRPV4) channels, ciliary machinery, and purinergic receptor remodeling. Sodium transport is reviewed with a focus on the epithelial sodium channel (ENaC), and the role of chloride-dependent fluid secretion in cystic fluid accumulation is discussed. In addition, we highlight the emerging promising concepts in the field, such as potassium transport, and suggest some new avenues for research related to electrolyte handling.

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          Most cited references144

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          TMEM16A confers receptor-activated calcium-dependent chloride conductance.

          Calcium (Ca(2+))-activated chloride channels are fundamental mediators in numerous physiological processes including transepithelial secretion, cardiac and neuronal excitation, sensory transduction, smooth muscle contraction and fertilization. Despite their physiological importance, their molecular identity has remained largely unknown. Here we show that transmembrane protein 16A (TMEM16A, which we also call anoctamin 1 (ANO1)) is a bona fide Ca(2+)-activated chloride channel that is activated by intracellular Ca(2+) and Ca(2+)-mobilizing stimuli. With eight putative transmembrane domains and no apparent similarity to previously characterized channels, ANO1 defines a new family of ionic channels. The biophysical properties as well as the pharmacological profile of ANO1 are in full agreement with native Ca(2+)-activated chloride currents. ANO1 is expressed in various secretory epithelia, the retina and sensory neurons. Furthermore, knockdown of mouse Ano1 markedly reduced native Ca(2+)-activated chloride currents as well as saliva production in mice. We conclude that ANO1 is a candidate Ca(2+)-activated chloride channel that mediates receptor-activated chloride currents in diverse physiological processes.
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            Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents.

            The human kidney is composed of roughly 1.2-million renal tubules that must maintain their tubular structure to function properly. In autosomal dominant polycystic kidney disease (ADPKD) cysts develop from renal tubules and enlarge independently, in a process that ultimately causes renal failure in 50% of affected individuals. Mutations in either PKD1 or PKD2 are associated with ADPKD but the function of these genes is unknown. PKD1 is thought to encode a membrane protein, polycystin-1, involved in cell-cell or cell-matrix interactions, whereas the PKD2 gene product, polycystin-2, is thought to be a channel protein. Here we show that polycystin-1 and -2 interact to produce new calcium-permeable non-selective cation currents. Neither polycystin-1 nor -2 alone is capable of producing currents. Moreover, disease-associated mutant forms of either polycystin protein that are incapable of heterodimerization do not result in new channel activity. We also show that polycystin-2 is localized in the cell in the absence of polycystin-1, but is translocated to the plasma membrane in its presence. Thus, polycystin-1 and -2 co-assemble at the plasma membrane to produce a new channel and to regulate renal tubular morphology and function.
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              Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells.

              Several proteins implicated in the pathogenesis of polycystic kidney disease (PKD) localize to cilia. Furthermore, cilia are malformed in mice with PKD with mutations in TgN737Rpw (encoding polaris). It is not known, however, whether ciliary dysfunction occurs or is relevant to cyst formation in PKD. Here, we show that polycystin-1 (PC1) and polycystin-2 (PC2), proteins respectively encoded by Pkd1 and Pkd2, mouse orthologs of genes mutated in human autosomal dominant PKD, co-distribute in the primary cilia of kidney epithelium. Cells isolated from transgenic mice that lack functional PC1 formed cilia but did not increase Ca(2+) influx in response to physiological fluid flow. Blocking antibodies directed against PC2 similarly abolished the flow response in wild-type cells as did inhibitors of the ryanodine receptor, whereas inhibitors of G-proteins, phospholipase C and InsP(3) receptors had no effect. These data suggest that PC1 and PC2 contribute to fluid-flow sensation by the primary cilium in renal epithelium and that they both function in the same mechanotransduction pathway. Loss or dysfunction of PC1 or PC2 may therefore lead to PKD owing to the inability of cells to sense mechanical cues that normally regulate tissue morphogenesis.
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                Author and article information

                Contributors
                Journal
                Clin Sci (Lond)
                Clin Sci (Lond)
                cs
                Clinical Science (London, England : 1979)
                Portland Press Ltd.
                0143-5221
                1470-8736
                November 2021
                09 November 2021
                : 135
                : 21
                : 2521-2540
                Affiliations
                [1 ]Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia
                [2 ]Saint-Petersburg State Chemical Pharmaceutical University, St. Petersburg, Russia
                [3 ]Department of Physiology, Augusta University, Augusta, GA, U.S.A.
                Author notes
                Correspondence: Daria V. Ilatovskaya ( dilatovskaya@ 123456augusta.edu )
                [*]

                These authors contributed equally to this work.

                Author information
                http://orcid.org/0000-0003-0137-471X
                http://orcid.org/0000-0002-5992-8693
                http://orcid.org/0000-0003-4832-4170
                Article
                CS20210370
                10.1042/CS20210370
                8589009
                34751394
                4cb0f8d7-d573-4ad2-b1d5-91bb3003b65a
                © 2021 The Author(s).

                This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY-NC-ND).

                History
                : 05 April 2021
                : 15 October 2021
                : 26 October 2021
                Page count
                Pages: 20
                Categories
                Molecular Bases of Health & Disease
                Cell Membranes, Excitation & Transport
                Review Articles

                Medicine
                electrolyte transport,ion channels,kidney,polycystic kidney disease,purinergic signaling,renal physiology

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