Journal Article

TNFα-induced IP<sub>3</sub>R1 expression through TNFR1/PC-PLC/PKCα and TNFR2 signalling pathways in human mesangial cell

Yu-rong Wang, Zhen-guo Li, Jin-long Fu, Zhao-Han Wang, Ying Wen and Pei Liu

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 26, issue 1, pages 75-83
Published in print January 2011 | ISSN: 0931-0509
Published online July 2010 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/gfq406
TNFα-induced IP3R1 expression through TNFR1/PC-PLC/PKCα and TNFR2 signalling pathways in human mesangial cell

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Background. Little information is available regarding the mechanisms involved in cytokine-induced type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) expression in human mesangial cells (HMCs) in the occurrence of hepatorenal syndrome (HRS). Over-expression of IP3R1 would enhance both IP3-binding activity and sensitivity. We hypothesize that it is possible that increased IP3R1, induced by TNFα, would lead to increased IP3 sensitivity in response to a variety of vasoconstrictors, and promote HMC contraction and thus lead to reduced GFP, promoting HRS occurrence and development.

Methods. Quantitative real-time polymerase chain reaction and immunoblot assay were used to examine the effects of TNFα on IP3R1 mRNA and protein expression. Several inhibitors of kinases, depletion PKC, over-expression of dominant-negative mutant of PKC and non-radioactive PKC assay were used to examine the mechanism of signal transduction of TNFα-regulated IP3R1 in HMCs.

Results. TNFα increased IP3R1 mRNA and protein expression in HMCs, an effect that was blocked by prolonged incubated chronic PMA, D609, safingol and also by transfection with domain-negative PKCα construct. TNFα activated and promoted autophosphorylation of the PKCα. In addition, both anti-TNFR1 and anti-TNFR2 antibodies blocked TNFα-induced IP3R1 protein expression, while only anti-TNFR1 antibodies but not anti-TNFR2 antibodies attenuated TNFα-induced PKCα activity.

Conclusions. TNFα increased the expression of IP3R1, and this was mediated, at least in part, through the TNFR1/PC-PLC/PKCα and TNFR2 signalling pathways in HMCs.

Keywords: IP3R1; PC-PLC; PKCα; TNFα; TNFR

Journal Article.  4336 words.  Illustrated.

Subjects: Nephrology

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