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Physiopathology of Signaling Transmission in Renal Diseases

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (31 March 2020) | Viewed by 41449

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Special Issue Editor

Prof. Giovanna Valenti

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Guest Editor

Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70124 Bari, Italy
Interests: signal transduction; renal diseases; GPCR signaling; water transport; renal aquaporins; vasopressin; vesicle trafficking

Special Issue Information

Dear Colleagues,

Signal transduction pathways integrate a variety of cell functions, including regulation of membrane transporters and channels. Conversely, altered intracellular signaling pathways underlie several diseases. Multiple renal diseases associated with organ failure and reduced survival result from chronic stimulation of G protein coupled receptors (GPCRs) or, conversely, to impaired signaling. These can have a genetic basis or acquired character. For example, chronic kidney diseases (CKD) can be secondary to the expression of many genes influenced by the genetic background in which they find themselves. In the kidney, disturbed signaling transmission can be involved in altered membrane transports leading to clinical disorders. In this scenario, recent findings suggest that targeting GPCR signaling can be a novel therapeutic approach for treating renal diseases.

In this Special Issue of Cells, we invite your contributions, either in the form of original research articles, reviews, or shorter perspective articles on all aspects related to the theme of “Physiopathology of Signaling Transmission in Renal Diseases”.

Relevant topics include but are not limited to:

Altered G protein-coupled receptor (GPCR) signaling pathways in renal diseases;
Physiophatological role of intracellular calcium signaling pathways in regulation of membrane transporters and channels;
Renal ciliopathies;
Regulation and dysregulation of renal membrane transporters and channels associated to renal diseases;
Chronic kidney diseases caused by defects in signaling.

Prof. Giovanna Valenti
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

G protein-coupled receptor (GPCR) signaling
genetic kidney diseases
calcium signaling pathways
chronic kidney diseases

Published Papers (10 papers)

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Research

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15 pages, 3487 KiB

Open AccessFeature PaperArticle

Adrenomedullin Inhibits Osmotic Water Permeability in Rat Inner Medullary Collecting Ducts

by Fuying Ma, Guangping Chen, Eva L. Rodriguez, Janet D. Klein, Jeff M. Sands and Yanhua Wang

Cells 2020, 9(12), 2533; https://doi.org/10.3390/cells9122533 - 24 Nov 2020

Cited by 7 | Viewed by 2209

Abstract

Adrenomedullin (ADM) is a vasodilator that causes natriuresis and diuresis. However, the direct effect of ADM on osmotic water permeability in the rat inner medullary collecting duct (IMCD) has not been tested. We investigated whether ADM and its ADM receptor components (CRLR, RAMP2, and 3) are expressed in rat inner medulla (IM) and whether ADM regulates osmotic water permeability in isolated perfused rat IMCDs. The mRNAs of ADM, CRLR, and RAMP2 and 3 were detected in rat IM. Abundant protein of CRLR and RAMP3 were also seen but RAMP2 protein level was extremely low. Adding ADM (100 nM) to the bath significantly decreased osmotic water permeability. ADM significantly decreased aquaporin-2 (AQP2) phosphorylation at Serine 256 (pS256) and increased it at Serine 261 (pS261). ADM significantly increased cAMP levels in IM. However, inhibition of cAMP by SQ22536 further decreased ADM-attenuated osmotic water permeability. Stimulation of cAMP by roflumilast increased ADM-attenuated osmotic water permeability. Previous studies show that ADM also stimulates phospholipase C (PLC) pathways including protein kinase C (PKC) and cGMP. We tested whether PLC pathways regulate ADM-attenuated osmotic water permeability. Blockade of either PLC by U73122 or PKC by rottlerin significantly augmented the ADM-attenuated osmotic water permeability and promoted pS256-AQP2 but did change pS261-AQP2. Inhibition of cGMP by L-NAME did not change AQP2 phosphorylation. In conclusion, ADM primarily binds to the CRLR-RAMP3 receptor to initiate signaling pathways in the IM. ADM reduced water reabsorption through a PLC-pathway involving PKC. ADM-attenuated water reabsorption may be related to decreased trafficking of AQP2 to the plasma membrane. cAMP is not involved in ADM-attenuated osmotic water permeability. Full article

(This article belongs to the Special Issue Physiopathology of Signaling Transmission in Renal Diseases)

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19 pages, 3489 KiB

Open AccessArticle

The Vasopressin Receptor 2 Mutant R137L Linked to the Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD) Signals through an Alternative Pathway that Increases AQP2 Membrane Targeting Independently of S256 Phosphorylation

by Marianna Ranieri, Maria Venneri, Tommaso Pellegrino, Mariangela Centrone, Annarita Di Mise, Susanna Cotecchia, Grazia Tamma and Giovanna Valenti

Cells 2020, 9(6), 1354; https://doi.org/10.3390/cells9061354 - 29 May 2020

Cited by 13 | Viewed by 3375

Abstract

NSIAD is a rare X-linked condition, caused by activating mutations in the AVPR2 gene coding for the vasopressin V2 receptor (V2R) associated with hyponatremia, despite undetectable plasma vasopressin levels. We have recently provided in vitro evidence that, compared to V2R-wt, expression of activating V2R mutations R137L, R137C and F229V cause a constitutive redistribution of the AQP2 water channel to the plasma membrane, higher basal water permeability and significantly higher basal levels of p256-AQP2 in the F229V mutant but not in R137L or R137C. In this study, V2R mutations were expressed in collecting duct principal cells and the associated signalling was dissected. V2R-R137L and R137C mutants had significantly higher basal pT269-AQP2 levels -independently of S256 and PKA-which were reduced to control by treatment with Rho kinase (ROCK) inhibitor. Interestingly, ROCK activity was found significantly higher in V2R-R137L along with activation of the Gα12/13–Rho–ROCK pathway. Of note, inhibition of ROCK reduced the basal elevated osmotic water permeability to control. To conclude, our data demonstrate for the first time that the gain-of-function mutation of the V2R, R137L causing NSIAD, signals through an alternative PKA-independent pathway that increases AQP2 membrane targeting through ROCK-induced phosphorylation at S/T269 independently of S256 of AQP2. Full article

(This article belongs to the Special Issue Physiopathology of Signaling Transmission in Renal Diseases)

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19 pages, 2177 KiB

Open AccessArticle

Concerted EP2 and EP4 Receptor Signaling Stimulates Autocrine Prostaglandin E₂ Activation in Human Podocytes

by Eva Mangelsen, Michael Rothe, Angela Schulz, Aikaterini Kourpa, Daniela Panáková, Reinhold Kreutz and Juliane Bolbrinker

Cells 2020, 9(5), 1256; https://doi.org/10.3390/cells9051256 - 19 May 2020

Cited by 7 | Viewed by 3973

Abstract

Glomerular hyperfiltration is an important mechanism in the development of albuminuria. During hyperfiltration, podocytes are exposed to increased fluid flow shear stress (FFSS) in Bowman’s space. Elevated Prostaglandin E2 (PGE₂) synthesis and upregulated cyclooxygenase 2 (Cox2) are associated with podocyte injury by FFSS. We aimed to elucidate a PGE₂ autocrine/paracrine pathway in human podocytes (hPC). We developed a modified liquid chromatography tandem mass spectrometry (LC/ESI-MS/MS) protocol to quantify cellular PGE₂, 15-keto-PGE₂, and 13,14-dihydro-15-keto-PGE₂ levels. hPC were treated with PGE₂ with or without separate or combined blockade of prostaglandin E receptors (EP), EP2, and EP4. Furthermore, the effect of FFSS on COX2, PTGER2, and PTGER4 expression in hPC was quantified. In hPC, stimulation with PGE₂ led to an EP2- and EP4-dependent increase in cyclic adenosine monophosphate (cAMP) and COX2, and induced cellular PGE₂. PTGER4 was downregulated after PGE₂ stimulation in hPC. In the corresponding LC/ESI-MS/MS in vivo analysis at the tissue level, increased PGE₂ and 15-keto-PGE₂ levels were observed in isolated glomeruli obtained from a well-established rat model with glomerular hyperfiltration, the Munich Wistar Frömter rat. COX2 and PTGER2 were upregulated by FFSS. Our data thus support an autocrine/paracrine COX2/PGE₂ pathway in hPC linked to concerted EP2 and EP4 signaling. Full article

(This article belongs to the Special Issue Physiopathology of Signaling Transmission in Renal Diseases)

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26 pages, 8852 KiB

Open AccessArticle

Sorting Nexin 27 Regulates the Lysosomal Degradation of Aquaporin-2 Protein in the Kidney Collecting Duct

by Hyo-Jung Choi, Hyo-Ju Jang, Euijung Park, Stine Julie Tingskov, Rikke Nørregaard, Hyun Jun Jung and Tae-Hwan Kwon

Cells 2020, 9(5), 1208; https://doi.org/10.3390/cells9051208 - 13 May 2020

Cited by 17 | Viewed by 4405

Abstract

Sorting nexin 27 (SNX27), a PDZ (Postsynaptic density-95/Discs large/Zonula occludens 1) domain-containing protein, cooperates with a retromer complex, which regulates intracellular trafficking and the abundance of membrane proteins. Since the carboxyl terminus of aquaporin-2 (AQP2c) has a class I PDZ-interacting motif (X-T/S-X-Φ), the role of SNX27 in the regulation of AQP2 was studied. Co-immunoprecipitation assay of the rat kidney demonstrated an interaction of SNX27 with AQP2. Glutathione S-transferase (GST) pull-down assays revealed an interaction of the PDZ domain of SNX27 with AQP2c. Immunocytochemistry of HeLa cells co-transfected with FLAG-SNX27 and hemagglutinin (HA)-AQP2 also revealed co-localization throughout the cytoplasm. When the PDZ domain was deleted, punctate HA-AQP2 labeling was localized in the perinuclear region. The labeling was intensively overlaid by Lysotracker staining but not by GM130 labeling, a cis-Golgi marker. In rat kidneys and primary cultured inner medullary collecting duct cells, the subcellular redistribution of SNX27 was similar to AQP2 under 1-deamino-8-D-arginine vasopressin (dDAVP) stimulation/withdrawal. Cell surface biotinylation assay showed that dDAVP-induced AQP2 translocation to the apical plasma membrane was unaffected after SNX27 knockdown in mpkCCD cells. In contrast, the dDAVP-induced AQP2 protein abundance was significantly attenuated without changes in AQP2 mRNA expression. Moreover, the AQP2 protein abundance was markedly declined during the dDAVP withdrawal period after stimulation under SNX27 knockdown, which was inhibited by lysosome inhibitors. Autophagy was induced after SNX27 knockdown in mpkCCD cells. Lithium-induced nephrogenic diabetes insipidus in rats revealed a significant downregulation of SNX27 in the kidney inner medulla. Taken together, the PDZ domain-containing SNX27 interacts with AQP2 and depletion of SNX27 contributes to the autophagy-lysosomal degradation of AQP2. Full article

(This article belongs to the Special Issue Physiopathology of Signaling Transmission in Renal Diseases)

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15 pages, 3934 KiB

Open AccessArticle

Lithium Chloride and GSK3 Inhibition Reduce Aquaporin-2 Expression in Primary Cultured Inner Medullary Collecting Duct Cells Due to Independent Mechanisms

by Marc Kaiser and Bayram Edemir

Cells 2020, 9(4), 1060; https://doi.org/10.3390/cells9041060 - 23 Apr 2020

Cited by 9 | Viewed by 3690

Abstract

Lithium chloride (LiCl) is a widely used drug for the treatment of bipolar disorders, but as a side effect, 40% of the patients develop diabetes insipidus. LiCl affects the activity of the glycogen synthase kinase 3 (GSK3), and mice deficient for GSK3β showed a reduction in the urine concentration capability. The cellular and molecular mechanisms are not fully understood. We used primary cultured inner medullary collecting duct cells to analyze the underlying mechanisms. LiCl and the inhibitor of GSK3 (SB216763) induced a decrease in the aquaporin-2 (Aqp2) protein level. LiCl induced downregulation of Aqp2 mRNA expression while SB216763 had no effect and TWS119 led to increase in expression. The inhibition of the lysosomal activity with bafilomycin or chloroquine prevented both LiCl- and SB216763-mediated downregulation of Aqp2 protein expression. Bafilomycin and chloroquine induced the accumulation of Aqp2 in lysosomal structures, which was prevented in cells treated with dibutyryl cyclic adenosine monophosphate (dbcAMP), which led to phosphorylation and membrane localization of Aqp2. Downregulation of Aqp2 was also evident when LiCl was applied together with dbcAMP, and dbcAMP prevented the SB216763-induced downregulation. We showed that LiCl and SB216763 induce downregulation of Aqp2 via different mechanisms. While LiCl also affected the mRNA level, SB216763 induced lysosmal degradation. Specific GSK3β inhibition had an opposite effect, indicating a more complex regulatory mechanism. Full article

(This article belongs to the Special Issue Physiopathology of Signaling Transmission in Renal Diseases)

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18 pages, 6107 KiB

Open AccessArticle

Chlorpromazine Induces Basolateral Aquaporin-2 Accumulation via F-Actin Depolymerization and Blockade of Endocytosis in Renal Epithelial Cells

by Richard Bouley, Naofumi Yui, Abby Terlouw, Pui W. Cheung and Dennis Brown

Cells 2020, 9(4), 1057; https://doi.org/10.3390/cells9041057 - 23 Apr 2020

Cited by 14 | Viewed by 4121

Abstract

We previously showed that in polarized Madin–Darby canine kidney (MDCK) cells, aquaporin-2 (AQP2) is continuously targeted to the basolateral plasma membrane from which it is rapidly retrieved by clathrin-mediated endocytosis. It then undertakes microtubule-dependent transcytosis toward the apical plasma membrane. In this study, we found that treatment with chlorpromazine (CPZ, an inhibitor of clathrin-mediated endocytosis) results in AQP2 accumulation in the basolateral, but not the apical plasma membrane of epithelial cells. In MDCK cells, both AQP2 and clathrin were concentrated in the basolateral plasma membrane after CPZ treatment (100 µM for 15 min), and endocytosis was reduced. Then, using rhodamine phalloidin staining, we found that basolateral, but not apical, F-actin was selectively reduced by CPZ treatment. After incubation of rat kidney slices in situ with CPZ (200 µM for 15 min), basolateral AQP2 and clathrin were increased in principal cells, which simultaneously showed a significant decrease of basolateral compared to apical F-actin staining. These results indicate that clathrin-dependent transcytosis of AQP2 is an essential part of its trafficking pathway in renal epithelial cells and that this process can be inhibited by selectively depolymerizing the basolateral actin pool using CPZ. Full article

(This article belongs to the Special Issue Physiopathology of Signaling Transmission in Renal Diseases)

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10 pages, 1500 KiB

Open AccessArticle

Aldosterone Decreases Vasopressin-Stimulated Water Reabsorption in Rat Inner Medullary Collecting Ducts

by Yanhua Wang, Fuying Ma, Eva L. Rodriguez, Janet D. Klein and Jeff M. Sands

Cells 2020, 9(4), 967; https://doi.org/10.3390/cells9040967 - 14 Apr 2020

Cited by 3 | Viewed by 3421

Abstract

Aldosterone indirectly regulates water reabsorption in the distal tubule by regulating sodium reabsorption. However, the direct effect of aldosterone on vasopressin-regulated water and urea permeability in the rat inner medullary collecting duct (IMCD) has not been tested. We investigated whether aldosterone regulates osmotic water permeability in isolated perfused rat IMCDs. Adding aldosterone (500 nM) to the bath significantly decreased osmotic water permeability in the presence of vasopressin (50 pM) in both male and female rat IMCDs. Aldosterone significantly decreased aquaporin-2 (AQP2) phosphorylation at S256 but did not change it at S261. Previous studies show that aldosterone can act both genomically and non-genomically. We tested the mechanism by which aldosterone attenuates osmotic water permeability. Blockade of gene transcription with actinomycin D did not reverse aldosterone-attenuated osmotic water permeability. In addition to AQP2, the urea transporter UT-A1 contributes to vasopressin-regulated urine concentrating ability. We tested aldosterone-regulated urea permeability in vasopressin-treated IMCDs. Blockade of gene transcription did not reverse aldosterone-attenuated urea permeability. In conclusion, aldosterone directly regulates water reabsorption through a non-genomic mechanism. Aldosterone-attenuated water reabsorption may be related to decreased trafficking of AQP2 to the plasma membrane. There may be a sex difference apparent in the inhibitory effect of aldosterone on water reabsorption in the inner medullary collecting duct. This study is the first to show a direct effect of aldosterone to inhibit vasopressin-stimulated osmotic water permeability and urea permeability in perfused rat IMCDs. Full article

(This article belongs to the Special Issue Physiopathology of Signaling Transmission in Renal Diseases)

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26 pages, 5691 KiB

Open AccessFeature PaperArticle

Cyclin-Dependent Kinase 18 Controls Trafficking of Aquaporin-2 and Its Abundance through Ubiquitin Ligase STUB1, Which Functions as an AKAP

by Alessandro Dema, Dörte Faust, Katina Lazarow, Marc Wippich, Martin Neuenschwander, Kerstin Zühlke, Andrea Geelhaar, Tamara Pallien, Eileen Hallscheidt, Jenny Eichhorst, Burkhard Wiesner, Hana Černecká, Oliver Popp, Philipp Mertins, Gunnar Dittmar, Jens Peter von Kries and Enno Klussmann

Cells 2020, 9(3), 673; https://doi.org/10.3390/cells9030673 - 10 Mar 2020

Cited by 18 | Viewed by 4385

Abstract

Arginine-vasopressin (AVP) facilitates water reabsorption in renal collecting duct principal cells through regulation of the water channel aquaporin-2 (AQP2). The hormone binds to vasopressin V2 receptors (V2R) on the surface of the cells and stimulates cAMP synthesis. The cAMP activates protein kinase A (PKA), which initiates signaling that causes an accumulation of AQP2 in the plasma membrane of the cells facilitating water reabsorption from primary urine and fine-tuning of body water homeostasis. AVP-mediated PKA activation also causes an increase in the AQP2 protein abundance through a mechanism that involves dephosphorylation of AQP2 at serine 261 and a decrease in its poly-ubiquitination. However, the signaling downstream of PKA that controls the localization and abundance of AQP2 is incompletely understood. We carried out an siRNA screen targeting 719 kinase-related genes, representing the majority of the kinases of the human genome and analyzed the effect of the knockdown on AQP2 by high-content imaging and biochemical approaches. The screening identified 13 hits whose knockdown inhibited the AQP2 accumulation in the plasma membrane. Amongst the candidates was the so far hardly characterized cyclin-dependent kinase 18 (CDK18). Our further analysis revealed a hitherto unrecognized signalosome comprising CDK18, an E3 ubiquitin ligase, STUB1 (CHIP), PKA and AQP2 that controls the localization and abundance of AQP2. CDK18 controls AQP2 through phosphorylation at serine 261 and STUB1-mediated ubiquitination. STUB1 functions as an A-kinase anchoring protein (AKAP) tethering PKA to the protein complex and bridging AQP2 and CDK18. The modulation of the protein complex may lead to novel concepts for the treatment of disorders which are caused or are associated with dysregulated AQP2 and for which a satisfactory treatment is not available, e.g., hyponatremia, liver cirrhosis, diabetes insipidus, ADPKD or heart failure. Full article

(This article belongs to the Special Issue Physiopathology of Signaling Transmission in Renal Diseases)

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Review

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19 pages, 2678 KiB

Open AccessReview

Calcium-Sensing Receptor and Regulation of WNK Kinases in the Kidney

by Daria S. Ostroverkhova, Junda Hu, Vadim V. Tarasov, Tatiana I. Melnikova, Yuri B. Porozov and Kerim Mutig

Cells 2020, 9(7), 1644; https://doi.org/10.3390/cells9071644 - 9 Jul 2020

Cited by 6 | Viewed by 4464

Abstract

The kidney is essential for systemic calcium homeostasis. Urinary calcium excretion can be viewed as an integrative renal response to endocrine and local stimuli. The extracellular calcium-sensing receptor (CaSR) elicits a number of adaptive reactions to increased plasma Ca²⁺ levels including the control of parathyroid hormone release and regulation of the renal calcium handling. Calcium reabsorption in the distal nephron of the kidney is functionally coupled to sodium transport. Apart from Ca²⁺ transport systems, CaSR signaling affects relevant distal Na⁺-(K⁺)-2Cl⁻ cotransporters, NKCC2 and NCC. NKCC2 and NCC are activated by a kinase cascade comprising with-no-lysine [K] kinases (WNKs) and two homologous Ste20-related kinases, SPAK and OSR1. Gain-of-function mutations within the WNK-SPAK/OSR1-NKCC2/NCC pathway lead to renal salt retention and hypertension, whereas loss-of-function mutations have been associated with salt-losing tubulopathies such as Bartter or Gitelman syndromes. A Bartter-like syndrome has been also described in patients carrying gain-of-function mutations in the CaSR gene. Recent work suggested that CaSR signals via the WNK-SPAK/OSR1 cascade to modulate salt reabsorption along the distal nephron. The review presented here summarizes the latest progress in understanding of functional interactions between CaSR and WNKs and their potential impact on the renal salt handling and blood pressure. Full article

(This article belongs to the Special Issue Physiopathology of Signaling Transmission in Renal Diseases)

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17 pages, 2973 KiB

Open AccessReview

Reactive Oxygen Species and Redox Signaling in Chronic Kidney Disease

by Maria V. Irazabal and Vicente E. Torres

Cells 2020, 9(6), 1342; https://doi.org/10.3390/cells9061342 - 28 May 2020

Cited by 152 | Viewed by 6765

Abstract

Chronic kidney disease (CKD) remains a worldwide public health problem associated with serious complications and increased mortality rates. Accumulating evidence indicates that elevated intracellular levels of reactive oxygen species (ROS) play a major role in the pathogenesis of CKD. Increased intracellular levels of ROS can lead to oxidation of lipids, DNA, and proteins, contributing to cellular damage. On the other hand, ROS are also important secondary messengers in cellular signaling. Consequently, normal kidney cell function relies on the “right” amount of ROS. Mitochondria and NADPH oxidases represent major sources of ROS in the kidney, but renal antioxidant systems, such as superoxide dismutase, catalase, or glutathione peroxidase counterbalance ROS-mediated injury. This review discusses the main sources of ROS and antioxidant systems in the kidney, and redox signaling pathways leading to inflammation and fibrosis, which result in abnormal kidney function and CKD progression. We further discuss the important role of the nuclear factor erythroid 2-related factor 2 (Nrf2) in regulating antioxidant responses, and other mechanisms of redox signaling. Full article

(This article belongs to the Special Issue Physiopathology of Signaling Transmission in Renal Diseases)

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