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

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          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 podo-cyte 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.

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          Chloroquine in cancer therapy: a double-edged sword of autophagy.

          Tomonori Kimura, Yoshitsugu Takabatake, Atsushi Takahashi … (2013)
          Autophagy is a homeostatic cellular recycling system that is responsible for degrading damaged or unnecessary cellular organelles and proteins. Cancer cells are thought to use autophagy as a source of energy in the unfavorable metastatic environment, and a number of clinical trials are now revealing the promising role of chloroquine, an autophagy inhibitor, as a novel antitumor drug. On the other hand, however, the kidneys are highly vulnerable to chemotherapeutic agents. Recent studies have shown that autophagy plays a protective role against acute kidney injury, including cisplatin-induced kidney injury, and thus, we suspect that the use of chloroquine in combination with anticancer drugs may exacerbate kidney damage. Moreover, organs in which autophagy also plays a homeostatic role, such as the neurons, liver, hematopoietic stem cells, and heart, may be sensitive to the combined use of chloroquine and anticancer drugs. Here, we summarize the functions of autophagy in cancer and kidney injury, especially focusing on the use of chloroquine to treat cancer, and address the possible side effects in the combined use of chloroquine and anticancer drugs.
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            Role of connexin 43 in different forms of intercellular communication - gap junctions, extracellular vesicles and tunnelling nanotubes.

            Teresa M Ribeiro-Rodrigues, Tania Martins-Marques, Sandrine Morel … (2017)
            Communication is important to ensure the correct and efficient flow of information, which is required to sustain active social networks. A fine-tuned communication between cells is vital to maintain the homeostasis and function of multicellular or unicellular organisms in a community environment. Although there are different levels of complexity, intercellular communication, in prokaryotes to mammalians, can occur through secreted molecules (either soluble or encapsulated in vesicles), tubular structures connecting close cells or intercellular channels that link the cytoplasm of adjacent cells. In mammals, these different types of communication serve different purposes, may involve distinct factors and are mediated by extracellular vesicles, tunnelling nanotubes or gap junctions. Recent studies have shown that connexin 43 (Cx43, also known as GJA1), a transmembrane protein initially described as a gap junction protein, participates in all these forms of communication; this emphasizes the concept of adopting strategies to maximize the potential of available resources by reutilizing the same factor in different scenarios. In this Review, we provide an overview of the most recent advances regarding the role of Cx43 in intercellular communication mediated by extracellular vesicles, tunnelling nanotubes and gap junctions.
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              Defective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy

              Thati Madhusudhan, Hongjie Wang, Wei Dong … (2015)
              Endoplasmic reticulum (ER) stress is associated with diabetic nephropathy (DN), but its pathophysiological relevance and the mechanisms that compromise adaptive ER signalling in podocytes remain unknown. Here we show that nuclear translocation of the transcription factor spliced X-box binding protein-1 (sXBP1) is selectively impaired in DN, inducing activating transcription factor-6 (ATF6) and C/EBP homology protein (CHOP). Podocyte-specific genetic ablation of XBP1 or inducible expression of ATF6 in mice aggravates DN. sXBP1 lies downstream of insulin signalling and attenuating podocyte insulin signalling by genetic ablation of the insulin receptor or the regulatory subunits phosphatidylinositol 3-kinase (PI3K) p85α or p85β impairs sXBP1 nuclear translocation and exacerbates DN. Corroborating our findings from murine DN, the interaction of sXBP1 with p85α and p85β is markedly impaired in the glomerular compartment of human DN. Thus, signalling via the insulin receptor, p85, and XBP1 maintains podocyte homeostasis, while disruption of this pathway impairs podocyte function in DN.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Med
                Journal ID (iso-abbrev): Int. J. Mol. Med
                Journal ID (publisher-id): IJMM
                Title: International Journal of Molecular Medicine
                Publisher: D.A. Spandidos
                ISSN (Print): 1107-3756
                ISSN (Electronic): 1791-244X
                Publication date (Print): November 2019
                Publication date (Electronic): 10 September 2019
                Publication date PMC-release: 10 September 2019
                Volume: 44
                Issue: 5
                Pages: 1781-1788
                Affiliations
                [1 ]Department of Pediatric Nephrology, 2nd Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210003
                [2 ]Department of Pediatrics, Yanan Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650000
                [3 ]Department of Nephrology, Comprehensive Laboratory, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, P.R. China
                Author notes
                Correspondence to: Dr Weihua Gan or Dr Aiqing Zhang, Department of Pediatric Nephrology, 2nd Affiliated Hospital of Nanjing Medical University, 262 Zhongshanbeilu, Nanjing, Jiangsu 210003, P.R. China, E-mail: weihuagan@ 123456njmu.edu.cn , E-mail: njaiqing@ 123456njmu.edu.cn
                [*]

                Contributed equally

                Article
                Publisher ID: ijmm-44-05-1781
                DOI: 10.3892/ijmm.2019.4335
                PMC ID: 6777687
                PubMed ID: 31545399
                SO-VID: 406489b1-cc41-4ad9-8b7f-a782c5f50dd4
                Copyright © Copyright: © Ji et al.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                Date received : 16 March 2019
                Date accepted : 23 August 2019
                Categories
                Subject: Articles

                Keywords: connexin 43,autophagy,podocyte injury,diabetic nephropathy,mammalian target of rapamycin signaling pathway
                Data availability:
                Keywords: connexin 43, autophagy, podocyte injury, diabetic nephropathy, mammalian target of rapamycin signaling pathway

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