Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
International Journal of Molecular Medicine
Join Editorial Board Propose a Special Issue
Print ISSN: 1107-3756 Online ISSN: 1791-244X
Journal Cover
November-2019 Volume 44 Issue 5

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
November-2019 Volume 44 Issue 5

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article Open Access

Connexin 43‑autophagy loop in the podocyte injury of diabetic nephropathy

  • Authors:
    • Jialing Ji
    • Yajie Zhao
    • Chen Na
    • Min Yang
    • Xianyi Zhu
    • Huimin Shi
    • Weihua Gan
    • Aiqing Zhang
  • View Affiliations / Copyright

    Affiliations: Department of Pediatric Nephrology, 2nd Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210003, P.R. China, Department of Pediatrics, Yanan Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650000, P.R. China, Department of Nephrology, Comprehensive Laboratory, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, P.R. China
    Copyright: © Ji et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 1781-1788
    |
    Published online on: September 10, 2019
       https://doi.org/10.3892/ijmm.2019.4335
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

The reduction of podocyte injury is a key strategy in controlling proteinuria, which is the main early clinical manifestation of diabetic nephropathy (DN). Impaired autophagic flux is the primary mechanism responsible for podocyte injury in DN. The aim of the present study was to elucidate the effect of connexin 43 (Cx43) on impaired autophagic flux in podocyte injury and to explore its molecular mechanism of action in DN. Sprague‑Dawley rats were administered streptozocin (STZ) to construct a DN animal model. Podocytes were incubated in media containing either buffer or high glucose (HG; 30 mM) for variable time periods. The podocytes were then examined and the mechanism of injury was investigated using an Annexin V/PI assay, immunofluorescence staining, western blotting, and RNA interference. In vivo, STZ‑induced DN rats with or without Cx43 knockdown were established to observe the role of Cx43 in autophagic flux and podocyte injury. We observed that HG induced podocyte injury, accompanied by increases in Cx43 expression and impaired autophagic flux, as evidenced by the accumulation of LC3II/LC3I and p62. Interestingly, the silencing of Cx43 expression ameliorated autophagic flux impairment and reduced podocyte injury via suppression of the mammalian target of rapamycin pathway. Furthermore, impaired autophagic flux also blocked the degradation of Cx43. In vitro studies indicated that higher numbers of Annexin V/PI‑positive podocytes, impaired autophagic flux and increased Cx43 expression were observed in HG‑induced podocyte injury relative to the control group. The pathogenic effect of Cx43 on impaired autophagic flux and podocyte injury was also confirmed by Cx43 knockdown. The present study provided preliminary evidence indicating that the interdependence of Cx43 and impaired autophagic flux represents a novel mechanism of podocyte injury in DN. Hence, the Cx43‑autophagy loop is a potentially relevant therapeutic target for the treatment of DN.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

View References

1 

Gnudi L, Coward RJ and Long DA: Diabetic nephropathy: Perspective on novel molecular mechanisms. Trends Endocrinol Metab. 27:820–830. 2016. View Article : Google Scholar : PubMed/NCBI

2 

Susztak K, Raff AC, Schiffer M and Böttinger EP: Glucose- induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes. 55:225–233. 2006. View Article : Google Scholar

3 

Madhusudhan T, Wang H, Dong W, Ghosh S, Bock F, Thangapandi VR, Ranjan S, Wolter J, Kohli S, Shahzad K, et al: Defective podocyte insulin signalling through p85-XBP-1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy. Nat Commun. 6:64962015. View Article : Google Scholar

4 

Long J, Badal SS, Ye Z, Wang Y, Ayanga BA, Galvan DL, Green NH, Chang BH, Overbeek PA and Danesh FR: Long noncoding RNA Tug1 regulates mitochondrial bioenergetics in diabetic nephropathy. J Clin Invest. 126:4205–4218. 2016. View Article : Google Scholar : PubMed/NCBI

5 

Mizushima N and Komatsu M: Autophagy: Renovation of cells and tissues. Cell. 147:728–741. 2011. View Article : Google Scholar : PubMed/NCBI

6 

Tagawa A, Yasuda M, Kume S, Yamahara K, Nakazawa J, Chin-Kanasaki M, Araki H, Araki S, Koya D, Asanuma K, et al: Impaired podocyte autophagy exacerbates proteinuria in diabetic nephropathy. Diabetes. 65:755–767. 2016. View Article : Google Scholar

7 

Liu Y, Zhang J, Wang Y and Zeng X: Apelin involved in progression of diabetic nephropathy by inhibiting autophagy in podocytes. Cell Death Dis. 8:e30062017. View Article : Google Scholar : PubMed/NCBI

8 

Kume S, Yamahara K, Yasuda M, Maegawa H and Koya D: Autophagy: Emerging therapeutic target for diabetic nephrop-athy. Semin Nephrol. 34:9–16. 2014. View Article : Google Scholar : PubMed/NCBI

9 

Ribeiro-Rodrigues TM, Martins-Marques T, Morel S, Kwak BR and Girão H: Role of connexin 43 in different forms of intercel-lular communication-gap junctions, extracellular vesicles and tunneling nanotubes. J Cell Sci. 130:3619–3630. 2017. View Article : Google Scholar : PubMed/NCBI

10 

Sawai K, Mukoyama M, Mori K, Yokoi H, Koshikawa M, Yoshioka T, Takeda R, Sugawara A, Kuwahara T, Saleem MA, et al: Redistribution of connexin43 expression in glomerular podocytes predicts poor renal prognosis in patients with type 2 diabetes and overt nephropathy. Nephrol Dial Transplant. 21:2472–2477. 2006. View Article : Google Scholar : PubMed/NCBI

11 

Yang M, Wang B, Li M and Jiang B: Connexin 43 is involved in aldosterone-induced podocyte injury. Cell Physiol Biochem. 34:1652–1662. 2014. View Article : Google Scholar : PubMed/NCBI

12 

Prakoura N, Kavvadas P and Chadjichristos CE: Connexin 43: A new therapeutic target against chronic kidney disease. Cell Physiol Biochem. 49:9852018. View Article : Google Scholar : PubMed/NCBI

13 

Murphy SF, Varghese RT, Lamouille S, Guo S, Pridham KJ, Kanabur P, Osimani AM, Sharma S, Jourdan J, Rodgers CM, et al: Connexin 43 inhibition sensitizes chemoresistant glioblastoma cells to temozolomide. Cancer Res. 76:139–149. 2016. View Article : Google Scholar :

14 

Zhang A, Han Y, Wang B, Li S and Gan W: Beyond gap junction channel function: The expression of Cx43 contributes to aldosterone-induced mesangial cell proliferation via the ERK1/2 and PKC pathways. Cell Physiol Biochem. 36:1210–1222. 2015. View Article : Google Scholar : PubMed/NCBI

15 

Wang B, Xu X, He X, Wang Z and Yang M: Berberine improved aldo-induced podocyte injury via inhibiting oxidative stress and endoplasmic reticulum stress pathways both in vivo and in vitro. Cell Physiol Biochem. 39:217–228. 2016. View Article : Google Scholar : PubMed/NCBI

16 

Bejarano E, Yuste A, Patel B, Stout RF Jr, Spray DC and Cuervo AM: Connexins modulate autophagosome biogenesis. Nat Cell Biol. 16:401–414. 2014. View Article : Google Scholar : PubMed/NCBI

17 

Kim YC and Guan KL: mTOR: A pharmacologic target for autophagy regulation. J Clin Invest. 125:25–32. 2015. View Article : Google Scholar : PubMed/NCBI

18 

Lichtenstein A, Minogue PJ, Beyer EC and Berthoud VM: Autophagy: A pathway that contributes to connexin degradation. J Cell Sci. 124:910–920. 2011. View Article : Google Scholar : PubMed/NCBI

19 

Martins-Marques T, Catarino S, Zuzarte M, Marques C, Matafome P, Pereira P and Girão H: Ischaemia-induced autophagy leads to degradation of gap junction protein connexin43 in cardiomyocytes. Biochem J. 467:231–245. 2015. View Article : Google Scholar : PubMed/NCBI

20 

Li C, Ye L, Yang L, Yu X, He Y, Chen Z, Li L and Zhang D: Rapamycin promotes the survival and adipogenesis of ischemia-challenged adipose derived stem cells by improving autophagy. Cell Physiol Biochem. 44:1762–1774. 2017. View Article : Google Scholar : PubMed/NCBI

21 

Kimura T, Takabatake Y, Takahashi A and Isaka Y: Chloroquine in cancer therapy: A double-edged sword of autophagy. Cancer Res. 73:3–7. 2013. View Article : Google Scholar : PubMed/NCBI

22 

Yasuda-Yamahara M, Kume S, Tagawa A, Maegawa H and Uzu T: Emerging role of podocyte autophagy in the progression of diabetic nephropathy. Autophagy. 11:2385–2386. 2015. View Article : Google Scholar : PubMed/NCBI

23 

Liu M, Liang K, Zhen J, Zhou M, Wang X, Wang Z, Wei X, Zhang Y, Sun Y, Zhou Z, et al: Sirt6 deficiency exacerbates podo-cyte injury and proteinuria through targeting Notch signaling. Nat Commun. 8:4132017. View Article : Google Scholar

24 

Kim SN, Kwon HJ, Im SW, Son YH, Akindehin S, Jung YS, Lee SJ, Rhyu IJ, Kim IY, Seong JK, et al: Connexin 43 is required for the maintenance of mitochondrial integrity in brown adipose tissue. Sci Rep. 7:71592017. View Article : Google Scholar : PubMed/NCBI

25 

Kroemer G: Autophagy: A druggable process that is deregulated in aging and human disease. J Clin Invest. 125:1–4. 2015. View Article : Google Scholar : PubMed/NCBI

26 

Choi AM, Ryter SW and Levine B: Autophagy in human health and disease. N Engl J Med. 368:651–662. 2013. View Article : Google Scholar : PubMed/NCBI

27 

Wang B, Ding W, Zhang M, Li H, Guo H, Lin L, Chen J and Gu Y: Role of FOXO1 in aldosterone-induced autophagy: A compensatory protective mechanism related to podocyte injury. Oncotarget. 7:45331–45351. 2016.PubMed/NCBI

28 

Haefliger JA, Demotz S, Braissant O, Suter E, Waeber B, Nicod P and Meda P: Connexins 40 and 43 are differentially regulated within the kidneys of rats with renovascular hypertension. Kidney Int. 60:190–201. 2001. View Article : Google Scholar : PubMed/NCBI

29 

Laplante M and Sabatini DM: mTOR signaling in growth control and disease. Cell. 149:274–293. 2012. View Article : Google Scholar : PubMed/NCBI

30 

Shimobayashi M and Hall MN: Making new contacts: The mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol. 15:155–162. 2014. View Article : Google Scholar : PubMed/NCBI

31 

Gödel M, Hartleben B, Herbach N, Liu S, Zschiedrich S, Lu S, Debreczeni-Mór A, Lindenmeyer MT, Rastaldi MP, Hartleben G, et al: Role of mTOR in podocyte function and diabetic nephrop-athy in humans and mice. J Clin Invest. 121:2197–2209. 2011. View Article : Google Scholar

32 

Cinà DP, Onay T, Paltoo A, Li C, Maezawa Y, De Arteaga J, Jurisicova A and Quaggin SE: Inhibition of MTOR disrupts autophagic flux in podocytes. J Am Soc Nephrol. 23:412–420. 2012. View Article : Google Scholar :

33 

Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, Adachi H, Adams CM, Adams PD, Adeli K, et al: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 12:1–222. 2016. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Ji J, Zhao Y, Na C, Yang M, Zhu X, Shi H, Gan W and Zhang A: Connexin 43‑autophagy loop in the podocyte injury of diabetic nephropathy. Int J Mol Med 44: 1781-1788, 2019.
APA
Ji, J., Zhao, Y., Na, C., Yang, M., Zhu, X., Shi, H. ... Zhang, A. (2019). Connexin 43‑autophagy loop in the podocyte injury of diabetic nephropathy. International Journal of Molecular Medicine, 44, 1781-1788. https://doi.org/10.3892/ijmm.2019.4335
MLA
Ji, J., Zhao, Y., Na, C., Yang, M., Zhu, X., Shi, H., Gan, W., Zhang, A."Connexin 43‑autophagy loop in the podocyte injury of diabetic nephropathy". International Journal of Molecular Medicine 44.5 (2019): 1781-1788.
Chicago
Ji, J., Zhao, Y., Na, C., Yang, M., Zhu, X., Shi, H., Gan, W., Zhang, A."Connexin 43‑autophagy loop in the podocyte injury of diabetic nephropathy". International Journal of Molecular Medicine 44, no. 5 (2019): 1781-1788. https://doi.org/10.3892/ijmm.2019.4335
Copy and paste a formatted citation
x
Spandidos Publications style
Ji J, Zhao Y, Na C, Yang M, Zhu X, Shi H, Gan W and Zhang A: Connexin 43‑autophagy loop in the podocyte injury of diabetic nephropathy. Int J Mol Med 44: 1781-1788, 2019.
APA
Ji, J., Zhao, Y., Na, C., Yang, M., Zhu, X., Shi, H. ... Zhang, A. (2019). Connexin 43‑autophagy loop in the podocyte injury of diabetic nephropathy. International Journal of Molecular Medicine, 44, 1781-1788. https://doi.org/10.3892/ijmm.2019.4335
MLA
Ji, J., Zhao, Y., Na, C., Yang, M., Zhu, X., Shi, H., Gan, W., Zhang, A."Connexin 43‑autophagy loop in the podocyte injury of diabetic nephropathy". International Journal of Molecular Medicine 44.5 (2019): 1781-1788.
Chicago
Ji, J., Zhao, Y., Na, C., Yang, M., Zhu, X., Shi, H., Gan, W., Zhang, A."Connexin 43‑autophagy loop in the podocyte injury of diabetic nephropathy". International Journal of Molecular Medicine 44, no. 5 (2019): 1781-1788. https://doi.org/10.3892/ijmm.2019.4335
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team