NF-kappa B modulates aquaporin-2 transcription in renal collecting duct principal cells
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- NF-kappa B modulates aquaporin-2 transcription in renal collecting duct principal cells
- Hasler, Udo; Leroy, Valeeie; Jeon, Un Sil; Bouley, Richard; Dimitrov, Mitko; Kim, Jeong Ah; Brown, Dennis; Kwon, H. Moo; Martin, Pierre-Yves; Feraille, Eric
- INDUCED NEPHROTIC SYNDROME; ENHANCER-BINDING PROTEIN; WATER CHANNEL EXPRESSION; DOWN-REGULATION; NULL MICE; ACTIVATION; MECHANISM; GENE; HYPERTONICITY; PERMEABILITY
- Issue Date
- AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
- JOURNAL OF BIOLOGICAL CHEMISTRY, v.283, no.42, pp.28095 - 28105
- Renal tubulo-interstitial inflammation is frequently associated with polyuria and urine concentration defects. This led us to investigate the effects of the major pro-inflammatory nuclear factor kappa B (NF-kappa B) pathway on aquaporin 2 (AQP2) expression by the collecting duct. Using immortalized collecting duct principal cells (mpkCCD(c14)), we found that, acting independently of vasopressin, activation of NF-kappa B by lipopolysaccharide (LPS) decreased AQP2 mRNA and protein levels in a time-and dose-dependent manner but did not decrease AQP2 mRNA stability. Consistently, constitutively active I kappa B kinase beta decreased AQP2 expression. The LPS-induced decrease in AQP2 mRNA levels was confirmed in rat kidney slices and was reproduced both under conditions of elevated cAMP concentration and V-2 receptor antagonism. Computer analysis of the AQP2 promoter revealed two putative kappa B elements. Mutation of either kappa B element abolished the LPS-induced decrease of luciferase activity in cells expressing AQP2 promoter-luciferase plasmid constructs. Chromatin immunoprecipitation revealed that LPS challenge decreased p65, increased p50 and p52, and had no effect on RelB and c-Rel binding to kappa B elements of the AQP2 promoter. RNA-mediated interference silencing of p65, p50, and p52 confirmed controlled AQP2 transcription by these NF-kappa B subunits. We additionally found that hypertonicity activated NF-kappa B in mpkCCD(c14) cells, an effect that may counteract the Tonicity-responsive enhancer binding protein (TonEBP)-dependent increase in AQP2 gene transcription. Taken together, these findings indicate that NF-kappa B is an important physiological regulator of AQP2 transcription.
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