Contribution of TFEB-mediated autophagy to tubulointerstitial fibrosis in mice with adenine-induced chronic kidney disease - 19/12/20
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Graphical abstract |
Highlights |
• | TFEB plays a detrimental role in the development of renal dysfunction in adenine-induced CKD. |
• | The mechanism involves in autophagic cell death induced by TFEB activation and consequent inflammation and fibrosis. |
• | Strategies targeting TFEB expression hold the promise for reducing renal injury to prevent CKD progression. |
Abstract |
Autophagy has been implicated in the pathogenesis of chronic kidney disease (CKD). Transcription factor EB (TFEB) is a master controller of autophagy. However, the pathophysiological roles of TFEB in modulating autophagy and tubulointerstitial injury in CKD are unknown. This study aimed to determine whether TFEB-mediated autophagy contributed to the tubulointerstitial injury in mice with CKD. After the mice were treated with an adenine diet (0.2 % adenine) for 8 weeks, the development of CKD was observed to be characterised by increased levels of plasma blood urea nitrogen (BUN), creatinine (Cre), tubulointerstitial inflammation and fibrosis. Immunohistochemical and Western blot analysis further revealed that TFEB and autophagy genes were significantly up-regulated in the kidney of the mice with adenine-induced CKD, and this increase was mostly found in the tubular epithelial cells. Interestingly, a similar expression pattern of TFEB-autophagy genes was observed in tubular epithelial cells in the kidney tissue of patients with immunoglobulin A (IgA) nephropathy. Moreover, a pathogenic role of TFEB in adenine-induced CKD was speculated because the pharmacological activation of TFEB by trehalose failed to protect mice from tubulointerstitial injuries. In the epithelioid clone of normal rat kidney cells (NRK-52E), the activation of TFEB by trehalose increased autophagy induction, cell death and inflammatory cytokine (Interleukin-6, IL-6) release. Collectively, these results suggested that the activation of TFEB-mediated autophagy might cause autophagic cell death and inflammation in tubular epithelial cells, contributing to renal fibrosis in adenine-induced CKD. This study provided novel insights into the pathogenic role of TFEB in CKD associated with a high purine diet.
El texto completo de este artículo está disponible en PDF.Keywords : Chronic kidney disease, Inflammation, Fibrosis, TFEB, Autophagy, Adenine diet
Esquema
Vol 133
Artículo 110949- janvier 2021 Regresar al númeroBienvenido a EM-consulte, la referencia de los profesionales de la salud.
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