Abstract
Cyclosporine A (CsA) is widely used as an immunosuppressor in transplantation. Previous studies reported that CsA induces autophagy and that chronic treatment with CsA results in accumulation of autophagosomes and reduced autophagic clearance. Autophagy is a prosurvival process that promotes recovery from acute kidney injury by degrading misfolded proteins produced in the kidney. In the present study, we used TMBIM6-expressing HK-2, human kidney tubular cells (TMBIM6 cells) and Tmbim6 knockout (tmbim6−/−) mice. When exposed to CsA, the TMBIM6 cells maintained autophagy activity by preventing autophagosome accumulation. With regard to signaling, PRKKA/AMPK phosphorylation and mechanistic target of rapamycin (serine/threonine kinase) complex 1 (MTORC1) expression and its downstream target TFEB (transcription factor EB), a lysosome biogenesis factor, were regulated in the TMBIM6 cells. Lysosomal activity was highly increased or stably maintained in the presence of TMBIM6. In addition, treatment of tmbim6−/− mice with CsA resulted in increased autophagosome formation and decreased lysosome formation and activity. We also found that tmbim6−/− mice were susceptible to CsA-induced kidney injury. Taken together, these results indicate that TMBIM6 protects against CsA-induced nephrotoxicity both in vitro and in vivo by inducing autophagy and activating lysosomes.
Highlights
Autophagy is a normal cellular process that may have a protective function during exposure to physiological or chemical stresses
We examined the effect of TMBIM6, a recently established regulator of endoplasmic reticulum (ER) stress and autophagy, on Cyclosporine A (CsA)-treated renal proximal tubule cells (HK-2 cells)
To examine whether TMBIM6 regulates autophagy in a CsA-treated human kidney cell line, we determined the expressions of LC3-II and SQSTM1 in human kidney 2 (HK-2) cells
Summary
Autophagy is a normal cellular process that may have a protective function during exposure to physiological or chemical stresses. Autophagy is activated during starvation to produce energy through lysosomal-mediated degradation of autophagosomes. Autophagosomes fuse with lysosomes and lysosomal hydrolytic enzymes break down the autophagosomes to produce amino acids, which are used for the synthesis of macromolecules and energy.[1,2] MAP1LC3B/LC3B Lysosomes are the main organelles involved in autophagosome processing. LC3-II, which is present in the lysosomal membrane and SQSTM1 are degraded by lysosomal acidic enzymes after fusion of the lysosome with the autophagosome. Incomplete maturation and decrease in the activity of lysosomes lead to decreased formation of autolysosomes and increased accumulation of SQSTM1 and LC3-II in autophagosomal membranes. Autophagy has protective effects,[5] and impaired induction of autophagy may induce cell death.[6,7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
