PMID- 26166660
OWN - NLM
STAT- MEDLINE
DCOM- 20160212
LR  - 20211203
IS  - 2284-0729 (Electronic)
IS  - 1128-3602 (Linking)
VI  - 19
IP  - 12
DP  - 2015 Jun
TI  - Apigenin inhibits indoxyl sulfate-induced endoplasmic reticulum stress and 
      anti-proliferative pathways, CHOP and IL-6/p21, in human renal proximal tubular 
      cells.
PG  - 2303-10
LID - 9106 [pii]
AB  - OBJECTIVE: Indoxyl sulfate (IS) has been reported to induce endoplasmic reticulum 
      (ER) stress in tubular cells and to inhibit the cell proliferation via ER stress 
      and ERK/IL-6/p21 pathways. This study has investigated the effect of apigenin on 
      IS-induced ER stress in immortalized human renal proximal tubular HK-2 cells. 
      MATERIALS AND METHODS: Human Kidney 2 (HK-2) cells were treated with IS (5 mM) in 
      the absence or presence of apigenin (10 muM) or salubrinal (20 muM) for indicated 
      times under the serum-free condition. Cell viability was evaluated by MTT assay. 
      The levels of protein expression and phosphorylation were evaluated by Western 
      blot analysis. RESULTS: In HK-2 cells, apigenin completely inhibited IS-induced 
      ER stress, as indicated by decreased expression of CHOP, ATF4 and GRP78, although 
      the phosphorylated level of eIF2alpha did not decrease. IS-induced expression levels 
      of IL-6 and p21 proteins were also inhibited by apigenin, with no significant 
      changes in ERK activation. The suppression of cell proliferation by IS was 
      abolished by salubrinal, an ER stress inhibitor, but not by apigenin. Apigenin 
      inhibited the phosphorylation of Akt and GSK-3beta in IS-treated HK-2 cells. The 
      phosphorylation of GSK-3beta, which was inhibited by apigenin, resulted in 
      hypo-phosphorylation of retinoblastoma (Rb) protein, which was associated with 
      the decrease in cyclin D1 expression. CONCLUSIONS: These results suggest that 
      apigenin may inhibit IS-induced ER stress and expression of IL-6 and p21 proteins 
      in HK-2 cells. It is most likely that apigenin, together with its inhibitory 
      effect on ER stress, may also suppress the cell growth by inducing the loss of Rb 
      phosphorylation, which was associated with the decrease in cyclin D1 expression 
      by GSK-3beta activation through the inhibition of PI3K/Akt pathway.
FAU - Jeon, B-J
AU  - Jeon BJ
AD  - Department of Pathology, College of Korean Medicine, Wonkwang University, Iksan, 
      Jeonbuk, Republic of Korea. omdjbh@wku.ac.kr.
FAU - Yang, H-M
AU  - Yang HM
FAU - Lyu, Y-S
AU  - Lyu YS
FAU - Pae, H-O
AU  - Pae HO
FAU - Ju, S-M
AU  - Ju SM
FAU - Jeon, B-H
AU  - Jeon BH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Italy
TA  - Eur Rev Med Pharmacol Sci
JT  - European review for medical and pharmacological sciences
JID - 9717360
RN  - 0 (CDKN1A protein, human)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p21)
RN  - 0 (DDIT3 protein, human)
RN  - 0 (Endoplasmic Reticulum Chaperone BiP)
RN  - 0 (HSPA5 protein, human)
RN  - 0 (IL6 protein, human)
RN  - 0 (Interleukin-6)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - 7V515PI7F6 (Apigenin)
RN  - N187WK1Y1J (Indican)
SB  - IM
MH  - Apigenin/*pharmacology
MH  - Cell Cycle/drug effects/physiology
MH  - Cell Line, Transformed
MH  - Cell Proliferation/drug effects/physiology
MH  - Cyclin-Dependent Kinase Inhibitor p21/antagonists & inhibitors/*biosynthesis
MH  - Endoplasmic Reticulum Chaperone BiP
MH  - Endoplasmic Reticulum Stress/drug effects/*physiology
MH  - Humans
MH  - Indican/antagonists & inhibitors/*toxicity
MH  - Interleukin-6/antagonists & inhibitors/*biosynthesis
MH  - Kidney Tubules, Proximal/drug effects/*metabolism
MH  - Transcription Factor CHOP/antagonists & inhibitors/*biosynthesis
EDAT- 2015/07/15 06:00
MHDA- 2016/02/13 06:00
CRDT- 2015/07/14 06:00
PHST- 2015/07/14 06:00 [entrez]
PHST- 2015/07/15 06:00 [pubmed]
PHST- 2016/02/13 06:00 [medline]
AID - 9106 [pii]
PST - ppublish
SO  - Eur Rev Med Pharmacol Sci. 2015 Jun;19(12):2303-10.