Fibronectin synthesis by high glucose level mediated proliferation of mouse embryonic stem cells: Involvement of ANG II and TGF-β1

doi:10.1002/jcp.22048

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Wiley InterScience

Journal of Cellular Physiology

Volume 223 Issue 2, Pages 397 - 407

Published Online: 28 Jan 2010

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Original Article

Fibronectin synthesis by high glucose level mediated proliferation of mouse embryonic stem cells: Involvement of ANG II and TGF-

Yun Hee Kim, Jung Min Ryu, Yu Jin Lee, Ho Jae Han^*

Department of Veterinary Physiology, Biotherapy Human Resources Center (BK 21), College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Korea

email: Ho Jae Han (hjhan@chonnam.ac.kr)

^*Correspondence to Ho Jae Han, Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Korea.

Yun Hee Kim and Jung Min Ryu equally contributed to the research.

Funded by:
Korea Science and Engineering Foundation (KOSEF); Grant Number: MEST 2009-0081395
Korea Government.

Abstract

The role of individual supplements necessary for the long-term self-renewal of embryonic stem (ES) cells is poorly characterized in feeder/serum-free culture systems. This study sought to characterize the relationship between the effects of glucose on ES cell proliferation and fibronectin (FN) synthesis, and to assess the mechanisms responsible for these cellular effects of glucose. Treatment of the two ES cells (ES-E14TG2a and ES-R1) with 25 mM glucose (high glucose) increased the expression levels of FN mRNA and protein. In addition, high glucose and ANG II synergistically increased FN expression level, which coincident with data showing that high glucose increased the mRNA expression of angiotensin II (ANG II) type 1 receptor (AT₁R), angiotensinogen, and FN, but not ANG II type 2 receptor. High glucose also increased the intracellular calcium (Ca²⁺) concentration and pan-protein kinase C (PKC) phosphorylation. Inhibition of the Ca²⁺/PKC pathway blocked high glucose-induced FN expression. High glucose or ANG II also synergistically increased transforming growth factor-beta1 (TGF-

₁) expression, while pretreatment with losartan abolished the high glucose-induced increase in TGF-

₁ production. Moreover, TGF-

₁-specific small interfering RNA inhibited high glucose-induced FN expression and c-Jun N-terminal kinase (JNK) activation. The JNK inhibitor SP600125 blocked high glucose-induced FN expression and inhibited cell cycle regulatory protein expression induced by high glucose or TGF-

₁. In this study, inhibition of AT₁R, Ca²⁺/PKC, TGF-

₁, JNK, FN receptor blocked the high glucose-induced DNA synthesis, increased the cell population in S phase, and the number of cells. It is concluded that high glucose increases FN synthesis through the ANG II or TGF-

Received: 14 October 2009; Accepted: 1 December 2009

Digital Object Identifier (DOI)

10.1002/jcp.22048 About DOI