Skip to main content
Hauptrubriken
CME Facharzt-Training Webinare Zeitschriften Bücher e.Medpedia Podcast
Service
Jobbörse Info & Hilfe
Fachgebiete
Anästhesiologie Allgemeinmedizin Arbeitsmedizin Augenheilkunde Chirurgie Dermatologie Gynäkologie und Geburtshilfe HNO Innere Medizin Kardiologie Neurologie Onkologie und Hämatologie Orthopädie und Unfallchirurgie Pädiatrie Pathologie Psychiatrie Radiologie Rechtsmedizin Urologie Zahnmedizin
Themen
Klimawandel und Gesundheit Neues aus dem Markt COVID-19 Praxis und Beruf Seltene Erkrankungen GOÄ & EBM Panorama
Sammlungen
Kasuistiken Algorithmen & Infografiken Blickdiagnosen Arthropedia FlapFinder (für Dermatochirurgen) Videos Kongressberichterstattung Medizin für Apothekerinnen und Apotheker Für Ärztinnen und Ärzte in Weiterbildung Für Medizinstudierende
Erweiterte Suche
Anmelden
nach oben
Diabetologia
Erschienen in: Diabetologia 2/2015

01.02.2015 | Review

Mind the gap: connexins and cell–cell communication in the diabetic kidney

verfasst von: Claire E. Hills, Gareth W. Price, Paul E. Squires

Erschienen in: Diabetologia | Ausgabe 2/2015

Einloggen, um Zugang zu erhalten

Abstract

Connexins, assembled as a hexameric connexon, form a transmembrane hemichannel that provides a conduit for paracrine signalling of small molecules and ions to regulate the activity and function of adjacent cells. When hemichannels align and associate with similar channels on opposing cells, they form a continuous aqueous pore or gap junction, allowing the direct transmission of metabolic and electrical signals between coupled cells. Regulation of gap junction synthesis and channel activity is critical for cell function, and a number of diseases can be attributed to changes in the expression/function of these important proteins. Diabetic nephropathy is associated with several complex metabolic and inflammatory responses characterised by defects at the molecular, cellular and tissue level. In both type 1 and type 2 diabetes, glycaemic injury of the kidney is the leading cause of end-stage renal failure, a consequence of multiple aetiologies, including increased deposition of extracellular matrix, glomerular hyperfiltration, albuminuria and tubulointerstitial fibrosis. In diabetic nephropathy, loss of connexin mediated cell–cell communication within the nephron may represent an early sign of disease; however, our current knowledge of the role of connexins in the diabetic kidney is sparse. This review highlights recent evidence demonstrating that maintenance of connexin-mediated cell–cell communication could benefit region-specific renal function in diabetic nephropathy and suggests that these proteins should be viewed as a tantalising novel target for therapeutic intervention.
Literatur
1.
Bosco D, Haefliger JA, Meda P (2011) Connexins: key mediators of endocrine function. Physiol Rev 91:1393–1445PubMedCrossRef
2.
Hanner F, Sorensen CM, Holstein-Rathlou NH, Peti-Peterdi J (2010) Connexins and the kidney. Am J Physiol Regul Integr Comp Physiol 298:R1143–R1155PubMedCentralPubMedCrossRef
3.
Oppermann M, Carota I, Schiessl I, Eisner C, Castrop H, Schnermann J (2013) Direct assessment of tubuloglomerular feedback responsiveness in connexin 40-deficient mice. Am J Physiol Ren Physiol 304:F1181–F1186CrossRef
4.
5.
Bobbie MW, Roy S, Trudeau K, Munger SJ, Simon AM, Roy S (2001) Reduced connexin 43 expression and its effect on the development of vascular lesions in retinas of diabetic mice. Invest Ophthalmol Vis Sci 51:3758–3763CrossRef
6.
Li AF, Roy S (2009) High glucose induced downregulation of connexin 43 expression promotes apoptosis in microvascular endothelial cells. Invest Ophthalmol Vis Sci 50:1400–1407PubMedCrossRef
7.
Zhang J, Hill CE (2005) Differential connexin expression in preglomerular and postglomerular vasculature: accentuation during diabetes. Kidney Int 68:1171–1185PubMedCrossRef
8.
Zhang JH, Kawashima S, Yokoyama M, Huang P, Hill CE (2006) Increased eNOS accounts for changes in connexin expression in renal arterioles during diabetes. Anat Rec A: Discov Mol Cell Evol Biol 288:1000–1008CrossRef
9.
Li AF, Sato T, Haimovici R, Okamoto T, Roy S (2003) High glucose alters connexin 43 expression and gap junction intercellular communication activity in retinal pericytes. Invest Ophthalmol Vis Sci 44:5376–5382PubMedCrossRef
10.
Sato T, Haimovici R, Kao R, Li AF, Roy S (2002) Downregulation of connexin 43 expression by high glucose reduces gap junction activity in microvascular endothelial cells. Diabetes 51:1565–1571PubMedCrossRef
11.
12.
Wada J, Makino H (2013) Inflammation and the pathogenesis of diabetic nephropathy. Clin Sci 124:139–152PubMedCrossRef
13.
Oyamada M, Takebe K, Oyamada Y (2013) Regulation of connexin expression by transcription factors and epigenetic mechanisms. Biochim Biophys Acta Biomembr 1828:118–133CrossRef
14.
15.
Kronengold J, Srinivas M, Verselis K (2012) The N-terminal half of the connexin protein contains the core elements of the pore and voltage gates. J Membr Biol 245:453–463PubMedCentralPubMedCrossRef
16.
Herve JC, Bourmeyster N, Sarrouilhe D, Duffy HS (2007) Gap junctional complexes: from partners to functions. Prog Biophys Mol Biol 94:29–65PubMedCrossRef
17.
18.
Nielsen MS, Nygaard Axelsen L, Sorgen PL, Verma V, Delmar M, Holstein-Rathlou NH (2012) Gap junctions. Compr Physiol 2:1981–2035PubMed
19.
20.
Goldberg GS, Alexander DB, Pellicena P, Zhang ZY, Tsuda H, Miller WT (2003) Src phosphorylates Cas on tyrosine 253 to promote migration of transformed cells. J Biol Chem 278:46533–46540PubMedCentralPubMedCrossRef
21.
Fujimoto K, Nagafuchi A, Tsukita S, Kuraoka A, Ohokuma A, Shibata Y (1997) Dynamics of connexins, E-cadherin and alpha-catenin on cell membranes during gap junction formation. J Cell Sci 110:311–322PubMed
22.
Defamie N, Chepied A, Mesnil M (2014) Connexins, gap junctions and tissue invasion. FEBS Lett 588:1331–1338PubMedCrossRef
23.
Pfenniger A, Wohlwend A, Kwak BR (2011) Mutations in connexin genes and disease. Eur J Clin Investig 41:103–116CrossRef
24.
Sahu G, Bera AK (2013) Contribution of intracellular calcium and pH in ischemic uncoupling of cardiac gap junction channels formed of connexins 43, 40, and 45: a critical function of C-terminal domain. PLoS One 8:e60506PubMedCentralPubMedCrossRef
25.
Tsuchida S, Arai Y, Kishida T et al (2013) Silencing the expression of connexin 43 decreases inflammation and joint destruction in experimental arthritis. J Orthop Res 31:525–530PubMedCrossRef
26.
Le Gal L, Alonso F, Wagner C et al (2014) Restoration of connexin 40 (Cx40) in renin-producing cells reduces the hypertension of Cx40 null mice. Hypertension 63:1198–1204PubMedCrossRef
27.
Firouzi M, Kok B, Spiering W et al (2006) Polymorphisms in human connexin40 gene promoter are associated with increased risk of hypertension in men. J Hypertens 24:325–330PubMedCrossRef
28.
29.
Tien T, Barrette KF, Chronopoulos A, Roy S (2013) Effects of high glucose-induced Cx43 downregulation on occludin and ZO-1 expression and tight junction barrier function in retinal endothelial cells. Invest Ophthalmol Vis Sci 3(54):6518–6525CrossRef
30.
Inoguchi T, Yu HY, Imamura M et al (2001) Altered gap junction activity in cardiovascular tissues of diabetes. Med Electron Microsc 34:86–91PubMedCrossRef
31.
Wagner C, Kurtz A (2013) Distribution and functional relevance of connexins in renin-producing cells. Pflugers Arch 465:71–77PubMedCrossRef
32.
Krattinger N, Capponi A, Mazzolai L et al (2007) Connexin40 regulates renin production and blood pressure. Kidney Int 72:814–822PubMedCrossRef
33.
Takenaka T, Inoue T, Kanno Y, Okada H, Meaney KR, Hill CE, Suzuki H (2008) Expression and role of connexins in the rat renal vasculature. Kidney Int 73:415–422PubMedCrossRef
34.
Haefliger JA, Castillo E, Waeber G et al (1997) Hypertension increases connexin43 in a tissue-specific manner. Circulation 18:1007–1014CrossRef
35.
Haefliger JA, Krattinger N, Martin D et al (2006) Connexin43-dependent mechanism modulates renin secretion and hypertension. J Clin Invest 116:405–413PubMedCentralPubMedCrossRef
36.
Gerl M, Kurt B, Kurtz A, Wagner C (2014) Connexin 43 is not essential for the control of renin synthesis and secretion. Pflugers Arch 466:1003–1009PubMedCrossRef
37.
Takenaka T, Inoue H, Okada Y et al (2011) Altered gap junctional communication and renal haemodynamics in Zucker fatty rat model of type 2 diabetes. Diabetologia 54:2192–2201PubMedCrossRef
38.
Loeffler I, Hopfer U, Koczan D, Wolf G (2011) Type VIII collagen modulates TGF-β1-induced proliferation of mesangial cells. J Am Soc Nephrol 22:649–663PubMedCentralPubMedCrossRef
39.
Cove-Smith A, Hendry BM (2008) The regulation of mesangial cell proliferation. Nephron Exp Nephrol 108:74–79CrossRef
40.
Yao J, Zhu Y, Morioka T, Oite T, Kitamura M (2007) Pathophysiological roles of gap junction in glomerular mesangial cells. J Membr Biol 217:123–130PubMedCrossRef
41.
Xie X, Lan T, Chang X et al (2013) Connexin43 mediates NF-κB signalling activation induced by high glucose in GMCs: involvement of c-Src. Cell Commun Signal 11:38PubMedCentralPubMedCrossRef
42.
Yao J, Morioka T, Oite T (2000) PDGF regulates gap junction communication and connexin43 phosphorylation by PI 3-kinase in mesangial cells. Kidney Int 57:1915–1926PubMedCrossRef
43.
Morioka T, Okada S, Nameta M et al (2013) Glomerular expression of connexin 40 and connexin 43 in rat experimental glomerulonephritis. Clin Exp Nephrol 17:191–204PubMedCrossRef
44.
Dalla Vestra M, Saller A, Mauer M, Fioretto P (2001) Role of mesangial expansion in the pathogenesis of diabetic nephropathy. J Nephrol 14:S51–S57PubMed
45.
Zhang X, Chen X, Wu D et al (2006) Downregulation of connexin 43 expression by high glucose induces senescence in glomerular mesangial cells. J Am Soc Nephrol 17:1532–1542PubMedCrossRef
46.
Liu L, Hu X, Cai GY et al (2012) High glucose-induced hypertrophy of mesangial cells is reversed by connexin43 overexpression via PTEN/Akt/mTOR signaling. Nephrol Dial Transplant 27:90–100PubMedCrossRef
47.
Giepmans BN, Hengeveld T, Postma FR, Moolenaar WH (2001) Interaction of c-Src with gap junction protein connexin-43: role in the regulation of cell-cell communication. J Biol Chem 276:8544–8549PubMedCrossRef
48.
Gilleron J, Fiorini C, Carette D et al (2008) Molecular reorganization of Cx43, ZO-1 and Src complexes during the endocytosis of gap junction plaques in response to a non-genomic carcinogen. J Cell Sci 121:4069–4078PubMedCrossRef
49.
Suzaki Y, Yoshizumi M, Kagami S et al (2004) BMK1 is activated in glomeruli of diabetic rats and in mesangial cells by high glucose conditions. Kidney Int 65:1749–1760PubMedCrossRef
50.
Prabhakar SS (2005) Pathogenic role of nitric oxide alterations in diabetic nephropathy. Curr Diabetes Rep 5:449–454CrossRef
51.
Awad A, Webb R, Carey R, Siragy HM (2004) Renal nitric oxide production is decreased in diabetic rats and improved by AT receptor blockade. J Hypertens 22:1571–1577PubMedCrossRef
52.
Prabhakar SP, Starnes J, Shi S, Lonis B, Tran R (2007) Diabetic nephropathy is associated with oxidative stress and decreased renal nitric oxide production. J Am Soc Nephrol 18:2945–2952PubMedCrossRef
53.
Mumtaz F, Dashwood M, Khan M, Thompson CS, Mikhailidis DP, Morgan RJ (2004) Down-regulation of nitric oxide synthase in the diabetic rabbit kidney: potential relevance to the early pathogenesis of diabetic nephropathy. Curr Med Res Opin 20:1–6PubMedCrossRef
54.
Yao J, Hiramatsu N, Zhu Y, Morioka T, Takeda M, Oite T, Kitamura M (2005) Nitric oxide-mediated regulation of connexin43 expression and gap junctional intercellular communication in mesangial cells. J Am Soc Nephrol 16:58–67PubMedCrossRef
55.
Lu D, Soleymani S, Madakshire R, Insel PA (2012) ATP released from cardiac fibroblasts via connexin hemichannels activates profibrotic P2Y2 receptors. FASEB J 26:2580–2591PubMedCentralPubMedCrossRef
56.
Retamal MA, Cortés CJ, Reuss L, Bennett MVL, Sáez JC (2006) S-Nitrosylation and permeation through connexin 43 hemichannels in astrocytes: induction by oxidant stress and reversal by reducing agents. Proc Natl Acad Sci U S A 103:4475–4480PubMedCentralPubMedCrossRef
57.
Hernández-Salinas R, Vielma AZ, Arismendi MN, Boric MP, Sáez JC, Velarde V (2013) Boldine prevents renal alterations in diabetic rats. J Diabetes Res 2013:593672PubMedCentralPubMedCrossRef
58.
Hillis GS, Duthie LA, Brown PA, Simpson JG, MacLeod AM, Haites NE (1997) Upregulation and co-localization of connexin43 and cellular adhesion molecules in inflammatory renal disease. J Pathol 182:373–379PubMedCrossRef
59.
Hillis GS, Duthie LA, Mlynski R et al (1997) The expression of connexin 43 in human kidney and cultured renal cells. Nephron 75:458–463PubMedCrossRef
60.
61.
Yan Q, Gao K, Chi Y, Li K et al (2012) NADPH oxidase-mediated upregulation of connexin43 contributes to podocyte injury. Free Radic Biol Med 15:1286–1297CrossRef
62.
Sawai K, Mukoyama M, Mori K et al (2006) Redistribution of connexin43 expression in glomerular podocytes predicts poor renal prognosis in patients with type 2 diabetes and overt nephropathy. Nephrol Dial Transplant 21:2472–2477PubMedCrossRef
63.
Hills CE, Squires PE (2011) The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy. Cytokine Growth Factor Rev 22:131–139PubMed
64.
Hills CE, Squires PE (2010) TGF-β1-induced epithelial-to-mesenchymal transition and therapeutic intervention in diabetic nephropathy. Am J Nephrol 31:68–74PubMedCrossRef
65.
Mege RM, Matsuzaki F, Gallin WJ, Goldberg JI, Cunningham BA, Edelman GM (1988) Construction of epithelioid sheets by transfection of mouse sarcoma cells with cDNAs for chicken cell adhesion molecules. Proc Natl Acad Sci U S A 85:7274–7278PubMedCentralPubMedCrossRef
66.
Jongen WM, Fitzgerald DJ, Asamoto M et al (1991) Regulation of connexin 43-mediated gap junctional intercellular communication by Ca2+ in mouse epidermal cells is controlled by E-cadherin. J Cell Biol 114:545–555PubMedCrossRef
67.
Hills CE, Siamantouras E, Smith SW, Cockwell P, Liu KK, Squires PE (2012) TGFβ modulates cell-to-cell communication in early epithelial-to-mesenchymal transition. Diabetologia 55:812–824PubMedCrossRef
68.
Hills CE, Kerr MI, Wall MJ, Squires PE (2013) Visfatin reduces gap junction mediated cell-to-cell communication in proximal tubule-derived epithelial cells. Cell Physiol Biochem 32:1200–1212PubMedCrossRef
69.
Hirschberg R (2005) Wound healing in the kidney: complex interactions in renal interstitial fibrogenesis. J Am Soc Nephrol 16:9–11PubMedCrossRef
70.
Liu Y (2006) Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int 69:213–217PubMedCrossRef
71.
Wright CS, Pollok S, Flint DJ, Brandner JM, Martin PE (2012) The connexin mimetic peptide Gap27 increases human dermal fibroblast migration in hyperglycemic and hyperinsulinemic conditions in vitro. J Cell Physiol 227:77–87PubMedCrossRef
72.
Qiu C, Coutinho P, Frank S et al (2003) Targeting connexin43 expression accelerates the rate of wound repair. Curr Biol 13:1697–1703PubMedCrossRef
73.
Wang CM, Lincoln J, Cook JE, Becker DL (2007) Abnormal connexin expression underlies delayed wound healing in diabetic skin. Diabetes 56:2809–2817PubMedCrossRef
74.
Mendoza-Naranjo A, Cormie P, Serrano AE et al (2012) Targeting Cx43 and N- cadherin, which are abnormally upregulated in venous leg ulcers, influences migration, adhesion and activation of Rho GTPases. PLoS One 7:e37374PubMedCentralPubMedCrossRef
75.
Abed A, Toubas J, Kavvadas P et al (2014) Targeting connexin 43 protects against the progression of experimental chronic kidney disease in mice. Kidney Int 86:768–779PubMedCrossRef
76.
Sipos A, Vargas SL, Toma I, Hanner F, Willecke K, Peti-Peterdi J (2009) Connexin 30 deficiency impairs renal tubular ATP release and pressure natriuresis. J Am Soc Nephrol 20:1724–1732PubMedCentralPubMedCrossRef
77.
Svenningsen P, Burford JL, Peti-Peterdi J (2013) ATP releasing connexin 30 hemichannels mediate flow-induced calcium signaling in the collecting duct. Front Physiol 4:292PubMedCentralPubMedCrossRef
78.
Hills CE, Bland R, Wheelans DC, Bennett J, Ronco PM, Squires PE (2006) Glucose-evoked alterations in connexin43-mediated cell-to-cell communication in human collecting duct: a possible role in diabetic nephropathy. Am J Physiol Renal Physiol 291:F1045–F1051PubMedCrossRef
79.
Hills CE, Bland R, Squires PE (2012) Functional expression of TRPV4 channels in human collecting duct cells: implications for secondary hypertension in diabetic nephropathy. Exp Diabetes Res 2012:936518PubMedCentralPubMedCrossRef
80.
Hills CE, Bland R, Bennett J, Ronco PM, Squires PE (2009) TGF-β1 mediates glucose-evoked up-regulation of connexin-43 cell-to-cell communication in HCD-cells. Cell Physiol Biochem 24:177–186PubMedCrossRef
81.
Lee YC, Yellowley CE, Li Z, Donahue HJ, Rannels DE (1997) Expression of functional gap junctions in cultured pulmonary alveolar epithelial cells. Am J Physiol 272:L1105–L1114PubMedCrossRef
Metadaten
Titel
Mind the gap: connexins and cell–cell communication in the diabetic kidney
verfasst von
Claire E. Hills
Gareth W. Price
Paul E. Squires
Publikationsdatum
01.02.2015
Verlag
Springer Berlin Heidelberg
Erschienen in
Diabetologia / Ausgabe 2/2015
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-014-3427-1

Weitere Artikel der Ausgabe 2/2015

Diabetologia 2/2015 Zur Ausgabe

Letter

Surrogate measures of insulin sensitivity vs the hyperinsulinaemic–euglycaemic clamp: a meta-analysis. Are there not some surrogate indexes lost in this story?

Article

A preclinical study on the efficacy and safety of a new vaccine against Coxsackievirus B1 reveals no risk for accelerated diabetes development in mouse models

Article

Glucose tolerance is associated with differential expression of microRNAs in skeletal muscle: results from studies of twins with and without type 2 diabetes

Letter

Surrogate measures of insulin sensitivity vs the hyperinsulinaemic–euglycaemic clamp: a meta-analysis. Are there not some surrogate indexes lost in this story? Reply to Bastard JP, Rabasa-Lhoret R, Laville M and Disse E [letter]

Article

Low-energy diets differing in fibre, red meat and coffee intake equally improve insulin sensitivity in type 2 diabetes: a randomised feasibility trial

Commentary

Surrogate measures of insulin resistance: does one size fit all?

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

26.04.2024 Hüft-TEP Nachrichten

Ob bei einer Notfalloperation nach Schenkelhalsfraktur eine Hemiarthroplastik oder eine totale Endoprothese (TEP) eingebaut wird, sollte nicht allein vom Alter der Patientinnen und Patienten abhängen. Auch über 90-Jährige können von der TEP profitieren.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Bei schweren Reaktionen auf Insektenstiche empfiehlt sich eine spezifische Immuntherapie

25.04.2024 Allergien und Intoleranzreaktionen Nachrichten

Insektenstiche sind bei Erwachsenen die häufigsten Auslöser einer Anaphylaxie. Einen wirksamen Schutz vor schweren anaphylaktischen Reaktionen bietet die allergenspezifische Immuntherapie. Jedoch kommt sie noch viel zu selten zum Einsatz.

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

25.04.2024 Hypertonie Nachrichten

Beginnen ältere Männer im Pflegeheim eine Antihypertensiva-Therapie, dann ist die Frakturrate in den folgenden 30 Tagen mehr als verdoppelt. Besonders häufig stürzen Demenzkranke und Männer, die erstmals Blutdrucksenker nehmen. Dafür spricht eine Analyse unter US-Veteranen.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen
Bildnachweise