Diverse functions of the inward-rectifying potassium channel Kir5.1 and its relationship with human diseases

Zhang, Chaojie; Guo, Jing

doi:10.3389/fphys.2023.1127893

Cited by 3 publications

(3 citation statements)

References 75 publications

(111 reference statements)

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“…Astrocytes display inwardly rectifying K + currents that have been attributed to K ir 4.1/5.1 heteromeric channels; these channels are directly inhibited by a decrease in intracellular pH such as occurs during a hypercapnic challenge in medullary astrocytes (Figure 6G) (Tanemoto et al, 2000;Xu et al, 2000;Pessia et al, 2001;Patterson et al, 2021;Zhang and Guo, 2023). Inhibition of the K + channel causes astrocytic depolarization, promoting NBCe1-mediated Na + and HCO 3 − uptake due to the electrogenic nature of the transporter (Wenker et al, 2010;Mulkey and Wenker, 2011).…”

Section: Channels In Rtn Area Astrocytesmentioning

confidence: 99%

Criteria for central respiratory chemoreceptors: experimental evidence supporting current candidate cell groups

Gonye,

Bayliss

2023

Front. Physiol.

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An interoceptive homeostatic system monitors levels of CO2/H+ and provides a proportionate drive to respiratory control networks that adjust lung ventilation to maintain physiologically appropriate levels of CO2 and rapidly regulate tissue acid-base balance. It has long been suspected that the sensory cells responsible for the major CNS contribution to this so-called respiratory CO2/H+ chemoreception are located in the brainstem—but there is still substantial debate in the field as to which specific cells subserve the sensory function. Indeed, at the present time, several cell types have been championed as potential respiratory chemoreceptors, including neurons and astrocytes. In this review, we advance a set of criteria that are necessary and sufficient for definitive acceptance of any cell type as a respiratory chemoreceptor. We examine the extant evidence supporting consideration of the different putative chemoreceptor candidate cell types in the context of these criteria and also note for each where the criteria have not yet been fulfilled. By enumerating these specific criteria we hope to provide a useful heuristic that can be employed both to evaluate the various existing respiratory chemoreceptor candidates, and also to focus effort on specific experimental tests that can satisfy the remaining requirements for definitive acceptance.

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Section: Channels In Rtn Area Astrocytesmentioning

confidence: 99%

Criteria for central respiratory chemoreceptors: experimental evidence supporting current candidate cell groups

Gonye,

Bayliss

2023

Front. Physiol.

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“…In many cases, calcium (Ca 2+ ) influx represents a convergent point for signaling [ 133 ]. Inward-rectifying (e.g., Kir) and depolarizing channels represent an important dimension of this dynamic [ 134 ]. As V mem shifts toward a depolarized state, the resting potential approaches the activation threshold for voltage-gated calcium channels, which can trigger cell migration, cell cycle progression, and proliferation.…”

Section: Biophysical Controlsmentioning

confidence: 99%

Biophysical control of plasticity and patterning in regeneration and cancer

Murugan,

Cariba,

Abeygunawardena

et al. 2023

Cell. Mol. Life Sci.

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Cells and tissues display a remarkable range of plasticity and tissue-patterning activities that are emergent of complex signaling dynamics within their microenvironments. These properties, which when operating normally guide embryogenesis and regeneration, become highly disordered in diseases such as cancer. While morphogens and other molecular factors help determine the shapes of tissues and their patterned cellular organization, the parallel contributions of biophysical control mechanisms must be considered to accurately predict and model important processes such as growth, maturation, injury, repair, and senescence. We now know that mechanical, optical, electric, and electromagnetic signals are integral to cellular plasticity and tissue patterning. Because biophysical modalities underly interactions between cells and their extracellular matrices, including cell cycle, metabolism, migration, and differentiation, their applications as tuning dials for regenerative and anti-cancer therapies are being rapidly exploited. Despite this, the importance of cellular communication through biophysical signaling remains disproportionately underrepresented in the literature. Here, we provide a review of biophysical signaling modalities and known mechanisms that initiate, modulate, or inhibit plasticity and tissue patterning in models of regeneration and cancer. We also discuss current approaches in biomedical engineering that harness biophysical control mechanisms to model, characterize, diagnose, and treat disease states.

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“…These proteins function as potassium channels that regulate the basolateral membrane potential of several kidney epithelial cells, including those lining the PT (PT), cortical thick ascending limb (cTAL), distal convoluted tubule (DCT), connecting tubule (CNT), and collecting duct (CCD) [4, 5]. Altered membrane potential through dysfunctions of Kir4.1/Kir5.1 or Kir4.2/Kir5.1 heteromeric channels leads to dysregulation of several membrane potential-dependent transport processes and protein activities [6, 7], resulting in a tubulopathy phenotype as observed in patients with KCNJ16 loss-of-function [2, 3]. In the PT, Kir4.2/Kir5.1 channels regulate the membrane potential in response to changes in intracellular pH.…”

Section: Introductionmentioning

confidence: 99%

A novelKCNJ16kidney organoid model recapitulates the disease phenotype and shows restoration of lipid accumulation upon treatment with statins

Sendino Garví,

van Slobbe,

Zaal

et al. 2023

Preprint

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BackgroundtheKCNJ16gene has been associated with a novel kidney tubulopathy phenotype,viz.disturbed acid-base homeostasis, hypokalemia and altered renal salt transport.KCNJ16encodes for Kir5.1, which together with Kir4.1 constitutes a potassium channel located at kidney tubular cell basolateral membranes. Preclinical studies provided mechanistical links between Kir5.1 and a disease phenotype, however, the disease pathology remains poorly understood. Here, we aimed at generating and characterizing a novel advancedin vitrohuman kidney model that recapitulates the disease phenotype to investigate further the pathophysiological mechanisms underlying the disease and potential therapeutic interventions.Methodswe used CRISPR/Cas9 to generateKCNJ16mutant (KCNJ16+/-andKCNJ16-/-) cell lines from healthy human induced pluripotent stem cells (iPSC)KCNJ16control (KCNJ16WT). The iPSCs were differentiated following an optimized protocol into kidney organoids in an air-liquid interface.ResultsKCNJ16-depleted kidney organoids showed transcriptomic and potential functional impairment of key voltage-dependent electrolyte and water-balance transporters. We observed cysts formation, lipid droplet accumulation and fibrosis upon Kir5.1 function loss. Furthermore, a large scale, glutamine tracer flux metabolomics analysis demonstrated thatKCNJ16-/-organoids display TCA cycle and lipid metabolism impairments. Drug screening revealed that treatment with statins, particularly the combination of simvastatin and C75, prevented lipid droplet accumulation and collagen-I deposition inKCNJ16-/-kidney organoids.Conclusionsmature kidney organoids represent a relevantin vitromodel for investigating the function of Kir5.1. We discovered novel molecular targets for this genetic tubulopathy and identified statins as a potential therapeutic strategy forKCNJ16defects in the kidney.Significance StatementIn this study, the use of CRISPR/Cas9 technology resulted in the establishment of aKCNJ16-depleted kidney organoid model, instrumental in elucidating the pathophysiology of the recently reportedKCNJ16-associated kidney tubulopathy. Our study substantiates the role of Kir5.1 (KCNJ16) in kidney disease, confirming already described phenotypes, as well as aiding to gain insight in the causal role of Kir5.1 loss in the disease phenotype. Our approach increases the knowledge onKCNJ16-related kidney phenotype, and it states the importance of combining CRISPR/Cas9 technology and advancedin vitromodels for complex disease modeling and therapy testing. Furthermore, we encourage the application of our approach to thein vitromodeling of rare and/or underrepresented genetic kidney diseases, for which the availability of patient material is limited.

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Diverse functions of the inward-rectifying potassium channel Kir5.1 and its relationship with human diseases

Cited by 3 publications

References 75 publications

Criteria for central respiratory chemoreceptors: experimental evidence supporting current candidate cell groups

Criteria for central respiratory chemoreceptors: experimental evidence supporting current candidate cell groups

Biophysical control of plasticity and patterning in regeneration and cancer

A novelKCNJ16kidney organoid model recapitulates the disease phenotype and shows restoration of lipid accumulation upon treatment with statins

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