Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Diabetologia
Published in: Diabetologia 8/2011

01-08-2011 | Article

Altered gap junctional communication and renal haemodynamics in Zucker fatty rat model of type 2 diabetes

Authors: T. Takenaka, T. Inoue, H. Okada, Y. Ohno, T. Miyazaki, D. J. Chaston, C. E. Hill, H. Suzuki

Published in: Diabetologia | Issue 8/2011

Login to get access

Abstract

Aims/hypothesis

We examined the link between altered gap junctional communication and renal haemodynamic abnormalities in diabetes in studies performed on Zucker lean (ZL) and the Zucker diabetic fatty (ZDF) rat model of type 2 diabetes.

Methods

The abundance of connexin (Cx) 37, 40 and 43 was assessed by western blot and immunohistochemistry. Renal haemodynamics was characterised with GAP peptides, which are Cx mimetics, to inhibit gap junctions as a probe in both strains.

Results

ZDF rats exhibited higher plasma glucose, 8-epi-prostaglandin F2α excretion, renal plasma flow and GFR than ZL rats. In ZDF rat kidney phosphorylation of Cx43 was enhanced compared with that in ZL rats. Immunohistochemical study revealed that the density of abundance of Cx37 in renin-secreting cells was significantly reduced in ZDF rats. Although renal autoregulation was markedly impaired in ZDF rats, it was preserved in ZL rats. GAP27 for Cx37,43 and for Cx40 impaired renal autoregulation in ZL rats, but failed to induce further alterations in renal autoregulation in ZDF rats.

Conclusions/interpretation

Our findings indicate that ZDF rats have glomerular hyperfiltration with impaired autoregulation. They also demonstrate enhanced phosphorylation of Cxs and reduced production of Cxs in ZDF rat kidney, especially of Cx37 in renin-secreting cells. Finally, our data suggest that an impairment of gap junctional communication in juxtaglomerular apparatus plays a role in altered renal autoregulation in diabetes.
Appendix
Available only for authorised users
Literature
1.
Severs NJ, Bruce AF, Dupont E, Rothery S (2008) Remodelling of gap junctions and connexin expression in diseased myocardium. Cardiovasc Res 1(80):9–19CrossRef
2.
Rummery NM, Hill CE (2004) Vascular gap junctions and implications for hypertension. Clin Exp Pharmacol Physiol 31:659–667PubMedCrossRef
3.
Haddock RE, Grayson TH, Brackenbury TD et al (2006) Endothelial coordination of cerebral vasomotion via myoendothelial gap junctions containing connexins 37 and 40. Am J Physiol 291:H2047–H2056
4.
Taugner R, Kirchheim H, Forssmann WG (1984) Myoendothelial contacts in glomerular arterioles and in renal interlobular arteries of rat, mouse and Tupaia belangeri. Cell Tissue Res 235:319–325PubMedCrossRef
5.
Takenaka T, Okada H, Kanno Y et al (2006) Exogenous 5′-nucleotidase improves glomerular autoregulation in Thy-1 nephritic rats. Am J Physiol 290:F844–F853
6.
Moore LC, Iijima K, Rich A, Casellas D, Goligorsky MS (1991) Communication of the tubuloglomerular feedback signal in the JGA. Kidney Int 32(Suppl):S45–S50
7.
Takenaka T, Hayashi K, Ikenaga H (2004) Blood pressure regulation and renal microcirculation. Contrib Nephrol 143:46–64PubMedCrossRef
8.
Kurtz L, Schweda F, de Wit C et al (2007) Lack of connexin 40 causes displacement of renin-producing cells from afferent arterioles to the extraglomerular mesangium. J Am Soc Nephrol 18:1103–1111PubMedCrossRef
9.
Wagner C, Kurtz L, Schweda F, Simon AM, Kurtz A (2009) Connexin 37 is dispensable for the control of the renin system and for positioning of renin-producing cells in the kidney. Pflugers Arch 459:151–158PubMedCrossRef
10.
Wagner C, de Wit C, Kurtz L, Grunberger C, Kurtz A, Schweda F (2007) Connexin40 is essential for the pressure control of renin synthesis and secretion. Circ Res 100:556–563PubMedCrossRef
11.
Takenaka T, Inoue T, Kanno Y et al (2008) Expression and role of connexins in the rat renal vasculature. Kidney Int 73:415–422PubMedCrossRef
12.
Takenaka T, Inoue T, Kanno Y, Okada H, Hill CE, Suzuki H (2008) Connexins 37 and 40 transduce purinergic signals mediating renal autoregulation. Am J Physiol 294:R1–R11CrossRef
13.
Saez JC, Berthoud VM, Branes MC, Martinez AD, Beyer EC (2003) Plasma membrane channels formed by connexins: their regulation and functions. Physiol Rev 83:1359–1400PubMed
14.
Hanner F, Sorensen CM, Holstein-Rathlou NH, Peti-Peterdi J (2010) Connexins and the kidney. Am J Physiol Regul Integr Comp Physiol 298:R1143–R1155PubMedCrossRef
15.
Solan JL, Lampe PD (2009) Connexin43 phosphorylation: structural changes and biological effects. Biochem J 419:261–272PubMedCrossRef
16.
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
17.
Kuroki T, Inoguchi T, Umeda F, Ueda F, Nawata H (1998) High glucose induces alteration of gap junction permeability and phosphorylation of connexin-43 in cultured aortic smooth muscle cells. Diabetes 47:931–936PubMedCrossRef
18.
Forster HG, ter Wee PM, Takenaka T, Hohman TC, Epstein M (1994) Impairment of afferent arteriolar myogenic responsiveness in the galactose-fed rat. Proc Soc Exp Biol Med 206:365–374PubMed
19.
Thomson SC, Deng A, Bao D, Satriano J, Blantz RC, Vallon V (2001) Ornithine decarboxylase, kidney size, and the tubular hypothesis of glomerular hyperfiltration in experimental diabetes. J Clin Invest 107:217–224PubMedCrossRef
20.
21.
Griffith TM, Chaytor AT, Edwards DH (2004) The obligatory link: role of gap junctional communication in endothelium-dependent smooth muscle hyperpolarization. Pharmacol Res 49:551–564PubMedCrossRef
22.
Matchkov VV, Rahman A, Bakker LM, Griffith TM, Nilsson H, Aalkjaer C (2006) Analysis of effects of connexin-mimetic peptides in rat mesenteric small arteries. Am J Physiol 291:H357–H367CrossRef
23.
Sandow SL, Looft-Wilson R, Doran B, Grayson TH, Segal SS, Hill CE (2003) Expression of homocellular and heterocellular gap junctions in hamster arterioles and feed arteries. Cardiovasc Res 60:643–653PubMedCrossRef
24.
Verma V, Due Larsen B, Coombs W et al (2010) Design and characterization of the first peptidomimetic molecule that prevents acidification-induced closure of cardiac gap junctions. Heart Rhythm 7:1491–1498PubMedCrossRef
25.
Rummery NM, Grayson TH, Hill CE (2005) Angiotensin-converting enzyme inhibition restores endothelial but not medial connexin expression in hypertensive rats. J Hypertens 23:317–328PubMedCrossRef
26.
Rummery NM, Hickey H, McGurk G, Hill CE (2002) Connexin37 is the major connexin expressed in the media of caudal artery. Arterioscler Thromb Vasc Biol 22:1427–1432PubMedCrossRef
27.
Inoue T, Okada H, Kobayashi T et al (2003) Hepatocyte growth factor counteracts transforming growth factor-beta1, through attenuation of connective tissue growth factor induction, and prevents renal fibrogenesis in 5/6 nephrectomized mice. FASEB J 17:268–270PubMed
28.
Ichiki A, Miyazaki T, Nodera M, Suzuki H, Yanagisawa H (2008) Ascorbate inhibits apoptosis of Kupffer cells during warm ischemia/reperfusion injury. Hepatogastroenterology 55:338–344PubMed
29.
Takenaka T, Mitchell KD, Navar LG (1993) Contribution of angiotensin II to renal hemodynamic and excretory responses to nitric oxide synthesis inhibition in the rat. J Am Soc Nephrol 4:1046–1053PubMed
30.
Takenaka T, Suzuki H, Ikenaga H et al (1994) Effects of a calcium channel blocker, nicardipine, on pressure-natriuresis in Dahl salt-sensitive rats. Clin Exp Hypertens 16:77–88PubMedCrossRef
31.
de Vriese AS, van de Voorde J, Lameire NH (2002) Effects of connexin-mimetic peptides on nitric oxide synthase- and cyclooxygenase-independent renal vasodilation. Kidney Int 61:177–185PubMedCrossRef
32.
Marsh SA, Powell PC, Agarwal A, Dell’Italia LJ, Chatham JC (2007) Cardiovascular dysfunction in Zucker obese and Zucker diabetic fatty rats: role of hydronephrosis. Am J Physiol 293:H292–H298
33.
Forbes JM, Soulis T, Thallas V et al (2001) Renoprotective effects of a novel inhibitor of advanced glycation. Diabetologia 44:108–114PubMedCrossRef
34.
Navar LG, Inscho EW, Majid SA, Imig JD, Harrison-Bernard LM, Mitchell KD (1996) Paracrine regulation of the renal microcirculation. Physiol Rev 76:425–536PubMed
35.
Griffin KA, Abu-Naser M, Abu-Amarah I, Picken M, Williamson GA, Bidani AK (2007) Dynamic blood pressure load and nephropathy in the ZSF1 (fa/fa cp) model of type 2 diabetes. Am J Physiol 293:F1605–F1613CrossRef
36.
Brännström K, Morsing P, Arendshorst WJ (1999) Candesartan normalizes exaggerated tubuloglomerular feedback activity in young spontaneously hypertensive rats. J Am Soc Nephrol 10(Suppl 11):S213–S219PubMed
37.
38.
Satriano J, Mansoury H, Deng A et al (2010) Transition of kidney tubule cells to a senescent phenotype in early experimental diabetes. Am J Physiol Cell Physiol 299:C374–C380PubMedCrossRef
39.
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
40.
Craven PA, DeRubertis FR (1989) Protein kinase C is activated in glomeruli from streptozotocin diabetic rats. Possible mediation by glucose. J Clin Invest 83:1667–1675PubMedCrossRef
41.
Cooper ME (2001) Interaction of metabolic and haemodynamic factors in mediating experimental diabetic nephropathy. Diabetologia 44:1957–1972PubMedCrossRef
42.
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
43.
Young EJ, Hill MA, Wiehler WB, Triggle CR, Reid JJ (2008) Reduced EDHF responses and connexin activity in mesenteric arteries from the insulin-resistant obese Zucker rat. Diabetologia 51:872–881PubMedCrossRef
44.
Earley S, Resta TC, Walker BR (2004) Disruption of smooth muscle gap junctions attenuates myogenic vasoconstriction of mesenteric resistance arteries. Am J Physiol 287:H2677–H2686
45.
Takenaka T, Harrison-Bernard L, Inscho EW, Carmines PK, Navar LG (1996) Autoregulation of afferent arteriolar blood flow in juxtamedullary nephrons. Am J Physiol 267:F879–F887
46.
Takenaka T, Suzuki H, Fujiwara K et al (1997) Cellular mechanisms mediating rat renal microvascular constriction by angiotensin II. J Clin Invest 100:2107–2114PubMedCrossRef
47.
Kim SM, Mizel D, Huang YG, Briggs JP, Schnermann J (2006) Adenosine as a mediator of macula densa-dependent inhibition of renin secretion. Am J Physiol Ren Physiol 290:F1016–F1023CrossRef
48.
Marshall SM (2004) Recent advances in diabetic nephropathy. Clin Med 4:277–282PubMed
49.
Just A, Kurtz L, de Wit C, Wagner C, Kurtz A, Arendshorst WJ (2009) Connexin 40 mediates the tubuloglomerular feedback contribution to renal blood flow autoregulation. J Am Soc Nephrol 20:1577–1585PubMedCrossRef
50.
Zhang J, Hill CE (2005) Differential connexin expression in preglomerular and postglomerular vasculature: accentuation during diabetes. Kidney Int 68:1171–1185PubMedCrossRef
Metadata
Title
Altered gap junctional communication and renal haemodynamics in Zucker fatty rat model of type 2 diabetes
Authors
T. Takenaka
T. Inoue
H. Okada
Y. Ohno
T. Miyazaki
D. J. Chaston
C. E. Hill
H. Suzuki
Publication date
01-08-2011
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 8/2011
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-011-2175-8

Other articles of this Issue 8/2011

Diabetologia 8/2011 Go to the issue

Article

mRNA of the pro-apoptotic gene BBC3 serves as a molecular marker for TNF-α-induced islet damage in humans

Article

Increased abundance of the adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif (APPL1) in patients with obesity and type 2 diabetes: evidence for altered adiponectin signalling

Article

Aldosterone decreases glucose-stimulated insulin secretion in vivo in mice and in murine islets

Article

Disturbed subjective sleep characteristics in adult patients with long-standing type 1 diabetes mellitus

Article

No evidence of an increased mortality risk associated with low levels of glycated haemoglobin in a non-diabetic UK population

Erratum

Erratum to: Increased serum potassium affects renal outcomes: a post hoc analysis of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits