BACKGROUND/AIMS: toll-like receptor 4 (TLR4) and its adaptor protein MyD88 play an important role in ischemia/reperfusion (I/R) injury in the kidney, and pituitary adenylate cyclase-activating polypeptide (PACAP) could ameliorate renal I/R injury. METHODS: primary cultures of proximal tubule epithelial cells (PTEC) were prepared from wild-type and MyD88(-/-) mice, and subjected to hypoxia in vitro. Acute kidney injury (AKI) was induced by I/R in vivo in wild-type mice only. RESULTS: hypoxia resulted in significant increases in cytokine production and apoptosis/necrosis in wild-type PTEC, but these responses were markedly blunted in MyD88(-/-) PTEC. Treatment with PACAP38 before or after hypoxia further suppressed the hypoxia-induced cytokine responses and apoptosis in both MyD88(+/+) and MyD88(-/-) PTEC cultures. PACAP38 significantly inhibited TLR4/MyD88/TRAF6 as well as TRIF and IRF3 expression in mouse kidney and PTEC, and inhibited the secretion and mRNA expression of cytokines in kidneys from mice after I/R, paralleling the cytokine responses in vitro. Moreover, treatment with PACAP38 protected mice from renal failure, histological damage, neutrophil influx and tubule cell apoptosis after I/R. CONCLUSION: our data reveal that the TLR4-mediated cytokine responses to hypoxia are primarily dependent on MyD88 signaling and highlight the pivotal role of MyD88-dependent mechanisms in the coordination of the innate immune responses to ischemic/hypoxic acute renal tubular injury. The renoprotective effect of PACAP in AKI involves both MyD88-dependent and -independent pathways. 2010 S. Karger AG, Basel.
BACKGROUND/AIMS: toll-like receptor 4 (TLR4) and its adaptor protein MyD88 play an important role in ischemia/reperfusion (I/R) injury in the kidney, and pituitary adenylate cyclase-activating polypeptide (PACAP) could ameliorate renal I/R injury. METHODS: primary cultures of proximal tubule epithelial cells (PTEC) were prepared from wild-type and MyD88(-/-) mice, and subjected to hypoxia in vitro. Acute kidney injury (AKI) was induced by I/R in vivo in wild-type mice only. RESULTS:hypoxia resulted in significant increases in cytokine production and apoptosis/necrosis in wild-type PTEC, but these responses were markedly blunted in MyD88(-/-) PTEC. Treatment with PACAP38 before or after hypoxia further suppressed the hypoxia-induced cytokine responses and apoptosis in both MyD88(+/+) and MyD88(-/-) PTEC cultures. PACAP38 significantly inhibited TLR4/MyD88/TRAF6 as well as TRIF and IRF3 expression in mouse kidney and PTEC, and inhibited the secretion and mRNA expression of cytokines in kidneys from mice after I/R, paralleling the cytokine responses in vitro. Moreover, treatment with PACAP38 protected mice from renal failure, histological damage, neutrophil influx and tubule cell apoptosis after I/R. CONCLUSION: our data reveal that the TLR4-mediated cytokine responses to hypoxia are primarily dependent on MyD88 signaling and highlight the pivotal role of MyD88-dependent mechanisms in the coordination of the innate immune responses to ischemic/hypoxic acute renal tubular injury. The renoprotective effect of PACAP in AKI involves both MyD88-dependent and -independent pathways. 2010 S. Karger AG, Basel.
Authors: Haofeng Ji; Yu Zhang; Xiu-da Shen; Feng Gao; Cynthia Y Huang; Catalina Abad; Ronald W Busuttil; James A Waschek; Jerzy W Kupiec-Weglinski Journal: Hepatology Date: 2013-01-18 Impact factor: 17.425
Authors: Rohit Upadhyay; Wei-Zhong Ying; Zannatul Nasrin; Hana Safah; Edgar A Jaimes; Wenguang Feng; Paul W Sanders; Vecihi Batuman Journal: JCI Insight Date: 2020-07-23