PMID- 11168928
OWN - NLM
STAT- MEDLINE
DCOM- 20010405
LR  - 20220408
IS  - 0085-2538 (Print)
IS  - 0085-2538 (Linking)
VI  - 59
IP  - 2
DP  - 2001 Feb
TI  - High glucose-induced PKC activation mediates TGF-beta 1 and fibronectin synthesis 
      by peritoneal mesothelial cells.
PG  - 463-70
AB  - BACKGROUND: Progressive peritoneal fibrosis, membrane hyperpermeability, and 
      ultrafiltration failure have been observed in long-term peritoneal dialysis (PD) 
      using glucose as an osmotic agent. High glucose activates protein kinase C (PKC), 
      which is one important signal pathway in the activation of transforming growth 
      factor-beta 1 (TGF-beta 1) and fibronectin (FN). To gain a better understanding 
      of mechanisms involved in peritoneal fibrosis, we examined the effects of high 
      glucose on human peritoneal mesothelial cell (HPMC) TGF-beta 1 and FN mRNA 
      expression and protein synthesis and determined the involvement of PKC in the 
      high glucose-induced HPMC activation. METHODS: Synchronized confluent HPMC were 
      incubated with different concentrations of glucose with and without inhibition of 
      PKC. PKC activity and diacylglycerol (DAG) levels were measured. The expression 
      of TGF-beta 1 and FN mRNAs by HPMC was measured by Northern blot analysis. 
      TGF-beta 1 protein was measured by enzyme-linked immunosorbent assay (ELISA) and 
      mink lung epithelial cell growth inhibition assay. FN protein was measured by 
      Western blot analysis and ELISA. RESULTS: PKC activity and DAG levels in HPMC 
      cultured under 50 mmol/L (high) glucose increased 2.3- and 2.0-fold, 
      respectively, that of 5.6 mmol/L (control) glucose at 24 hours and this was 
      sustained up to 72 hours. The expression of TGF-beta 1 and FN mRNA by HPMC 
      cultured under high glucose increased 1.6- and 1.7-fold, respectively, that of 
      control values at 24 hours. TGF-beta bioactivity as well as protein content in 
      heat-activated conditioned media from high glucose was significantly higher than 
      that of control values at 24 and 48 hours. FN protein also increased in response 
      to high glucose, as measured by Western blot analysis and ELISA. PKC activator 
      phorbol 12-myristate 13-acetate (PMA) induced 2.2- and 1.4-fold increase in 
      TGF-beta 1 and FN mRNA expression, respectively. Depletion of PKC and calphostin 
      C, a PKC inhibitor, effectively prevented both PMA and high glucose-induced, but 
      not constitutive, expression of TGF-beta 1 and FN. CONCLUSION: The present data 
      demonstrate that high glucose up-regulates TGF-beta 1 and FN synthesis by HPMC, 
      and that this high glucose-induced up-regulation is largely mediated by PKC. 
      These results suggest that activation of PKC by high glucose in conventional PD 
      solutions may constitute an important signal for activation of HPMC, leading to 
      progressive accumulation of extracellular matrix and eventual peritoneal 
      fibrosis.
FAU - Ha, H
AU  - Ha H
AD  - Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea.
FAU - Yu, M R
AU  - Yu MR
FAU - Lee, H B
AU  - Lee HB
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Kidney Int
JT  - Kidney international
JID - 0323470
RN  - 0 (Diglycerides)
RN  - 0 (Fibronectins)
RN  - 0 (RNA, Messenger)
RN  - 0 (TGFB1 protein, human)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (Transforming Growth Factor beta1)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Cells, Cultured
MH  - Diglycerides/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Activation/physiology
MH  - Epithelial Cells/metabolism
MH  - Fibronectins/*biosynthesis/genetics
MH  - Glucose/*administration & dosage/pharmacology
MH  - Humans
MH  - Peritoneum/cytology/*metabolism
MH  - Protein Kinase C/*metabolism/physiology
MH  - RNA, Messenger/metabolism
MH  - Transforming Growth Factor beta/*biosynthesis/genetics
MH  - Transforming Growth Factor beta1
MH  - Up-Regulation
EDAT- 2001/02/13 11:00
MHDA- 2001/04/06 10:01
CRDT- 2001/02/13 11:00
PHST- 2001/02/13 11:00 [pubmed]
PHST- 2001/04/06 10:01 [medline]
PHST- 2001/02/13 11:00 [entrez]
AID - S0085-2538(15)47496-4 [pii]
AID - 10.1046/j.1523-1755.2001.059002463.x [doi]
PST - ppublish
SO  - Kidney Int. 2001 Feb;59(2):463-70. doi: 10.1046/j.1523-1755.2001.059002463.x.