TLR2 and TLR4 play opposite role in autophagy associated with cisplatin-induced acute kidney injury

Andrade-Silva, Magaiver; Cenedeze, Marcos Antônio; Perandini, Luiz Augusto; Felizardo, Raphael José Ferreira; Watanabe, Ingrid Kazue Mizuno; Agudelo, Juan Sebastián Henao; Castoldi, Ângela; Gonçalves, Giselle Martins; Origassa, Clarice Silvia Taemi; Semedo, Patrícia; Hiyane, Meire Ioshie; Foresto-Neto, Orestes; Malheiros, Denise Maria Avancini Costa; Reis, Marlene Antônia dos; Fujihara, Clarice Kazue; Zatz, Roberto; Pacheco-Silva, Álvaro; Câmara, Niels Olsen Saraiva; Almeida, Danilo Cândido de

doi:10.1042/cs20170262

Cited by 53 publications

(62 citation statements)

References 50 publications

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“…TLR signaling pathways play an important role in AKI, and TLR2 but not TLR4 plays a protective role in cisplatin‐induced AKI . The protective role of TLR2 is associated with autophagy and HO‐1.…”

Section: Discussionmentioning

confidence: 99%

TLR2 protects cisplatin‐induced acute kidney injury associated with autophagy via PI3K/Akt signaling pathway

Shen

Zhang

et al. 2018

J of Cellular Biochemistry

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Toll-like receptors (TLRs), which are essential components of the innate immune response, play an important role in acute kidney injury (AKI). Toll-like receptor 2 (TLR2) is constitutively expressed in tubular epithelial cells of the kidney and participates in cisplatin-induced AKI. The autophagy is a dynamic catabolic process that maintains intracellular homeostasis, which is involved in the pathogenesis of AKI. Recent studies demonstrate that PI3K/Akt signaling pathway regulates autophagy in response to various stimuli. Therefore, we propose that cisplatin might activate TLR2, which subsequently phosphorylates PI3K/Akt, leading to enhanced autophagy of renal tubular epithelial cells and protecting cisplatin-induced AKI. We found that TLR2 expression was significantly increased in the kidney after the cisplatin treatment. TLR2deficient mice exacerbated renal injury in cisplatin-induced AKI, with higher serum creatinine and blood urea nitrogen, more severe morphological injury compared with that of wild-type mice. In vitro, we found that inhibition of TLR2 reduced tubular epithelial cell autophagy after the cisplatin treatment.Mechanistically, TLR2 inhibited autophagy via activating PI3K/Akt signaling pathway in renal tubular epithelial cells after the cisplatin treatment. Take together, these results suggest that TLR2 may protect cisplatin-induced AKI by activating autophagy via PI3K/Akt signaling pathway. K E Y W O R D S acute kidney injury, autophagy, cisplatin, TLR2 J Cell Biochem. 2019;120:4366-4374. wileyonlinelibrary.com/journal/jcb 4366 | F I G U R E 6 Activation of TLR2 signaling using Pam3Cys further increases PI3K and Akt phosphorylation of renal tubular epithelial cells after the cisplatin treatment in vitro. A, Representative Western blots showed PI3K/Akt protein and phosphorylation of PI3K/AKT in vehicle or TLR2 agonist Pam3Cys pretreated renal tubular epithelial cells after the cisplatin (10 μg/ml, 6 hours) or sham treatment in vitro. B, Quantitative analysis of the ratio of phosphorylated Akt/total Akt and the ratio of phosphorylated PI3K/total PI3K. *P < 0.05 versus Vehicle Sham; + P < 0.05 versus Pam3Cys Cisplatin; # P < 0.05 versus Vehicle Cisplatin. n = 4 in each group. TLR2, toll-like receptor 2 SHEN ET AL. | 4373 ORCID Manli Li

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Section: Discussionmentioning

confidence: 99%

TLR2 protects cisplatin‐induced acute kidney injury associated with autophagy via PI3K/Akt signaling pathway

Shen

Zhang

et al. 2018

J of Cellular Biochemistry

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“…Toll-like receptors (TLRs), membrane passing proteins, are abundantly expressed in immune cells and renal tissue, and considered as autophagy mediators. For instance, it was reported that TLR2 induced autophagy in acute kidney injury model made by cisplatin and improved the global renal tissue parameters [124]. Wen et al found that TLR2 and TLR4 were up-regulated in hippocampus neurons of epilepsy mice.…”

Section: Cross-regulation By Toll-like Receptor-ligand Signal Pathwaymentioning

confidence: 99%

Exosomal cargos modulate autophagy in recipient cells via different signaling pathways

et al. 2020

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Vesicular system of mammalian cells is composed of two intracellular and extracellular vesicles systems, which contributes to the intra/intercellular communication and cellular homeostasis. These systems mediate transferring of biological molecules like proteins, nucleic acids, and lipids inside the cytoplasm, and between the cells. By the present study, authors describe molecular crosslink between exosome biogenesis and autophagy and take a certain focus on the autophagic cargos of exosomes and signaling pathways involved in exosome-induced autophagy in target cells and vice versa. Autophagy the generation of double-phospholipid vesicles, is a process that engulfs damaged proteins and organelles, share molecular similarity and function synergy with exosomes biogenesis for degradation or exocytosis of certain cargo. Exosomes, the smallest subtype of extracellular vesicles, originating from the membrane of the multivesicular body located inside cells demonstrate key roles in the intracellular and intercellular communication. Growing evidence demonstrates the interaction between exosome biogenesis and autophagy both at intertwined molecular pathways and crossbred vesicles known as amphisomes. Crosstalk between exosome biogenesis and autophagy contributes to maintain cellular homeostasis under external and internal stresses. Moreover, these processes can modulate each other via different signaling pathways. Exosomes contain autophagic cargos that induce autophagy via the cascade of molecular events in target cells, which called here exosome-induced autophagy. Taken together, crosstalk between exosome biogenesis and autophagy plays pivotal roles in cell homeostasis. Shedding light on the interaction between endomembrane systems may promote our knowledge about the relation between exosome and autophagy pathways in lysosome-related disorders against treatments; proposing a theoretical approach for therapy.

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“…The interaction of Toll-like receptors (TLR2 and TLR4), cisplatin-induced AKI, and HO-1 has been recently studied [86]. In response to cisplatin, TLR2 deficiency worsens renal injury, while these effects were not observed in TLR4-deficient mice.…”

Section: Ho-1 and Autophagymentioning

confidence: 99%

New insights into the role of heme oxygenase-1 in acute kidney injury

Nath

Agarwal

2020

Kidney Res Clin Pract

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TLR2 and TLR4 play opposite role in autophagy associated with cisplatin-induced acute kidney injury

Cited by 53 publications

References 50 publications

TLR2 protects cisplatin‐induced acute kidney injury associated with autophagy via PI3K/Akt signaling pathway

TLR2 protects cisplatin‐induced acute kidney injury associated with autophagy via PI3K/Akt signaling pathway

Exosomal cargos modulate autophagy in recipient cells via different signaling pathways

New insights into the role of heme oxygenase-1 in acute kidney injury

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