In:
American Journal of Nephrology, S. Karger AG, Vol. 32, No. 6 ( 2010), p. 522-532
Abstract:
〈 i 〉 Background/Aims: 〈 /i 〉 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. 〈 i 〉 Methods: 〈 /i 〉 Primary cultures of proximal tubule epithelial cells (PTEC) were prepared from wild-type and MyD88 〈 sup 〉 –/– 〈 /sup 〉 mice, and subjected to hypoxia in vitro. Acute kidney injury (AKI) was induced by I/R in vivo in wild-type mice only. 〈 i 〉 Results: 〈 /i 〉 Hypoxia resulted in significant increases in cytokine production and apoptosis/necrosis in wild-type PTEC, but these responses were markedly blunted in MyD88 〈 sup 〉 –/– 〈 /sup 〉 PTEC. Treatment with PACAP38 before or after hypoxia further suppressed the hypoxia-induced cytokine responses and apoptosis in both MyD88 〈 sup 〉 +/+ 〈 /sup 〉 and MyD88 〈 sup 〉 –/– 〈 /sup 〉 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. 〈 i 〉 Conclusion: 〈 /i 〉 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.
Type of Medium:
Online Resource
ISSN:
0250-8095
,
1421-9670
Language:
English
Publisher:
S. Karger AG
Publication Date:
2010
detail.hit.zdb_id:
1468523-1
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