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

Ji,Jialing; Zhao,Yajie; Na,Chen; Yang,Min; Zhu,Xianyi; Shi,Huimin; Gan,Weihua; Zhang,Aiqing

doi:10.3892/ijmm.2019.4335

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
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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
Published online on: September 10, 2019 https://doi.org/10.3892/ijmm.2019.4335
Pages: 1781-1788
Copyright: © Ji et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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 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.

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