Induction of MIF synthesis and secretion by tubular epithelial cells: a novel action of angiotensin II.
BACKGROUND
Angiotensin II (Ang II) plays an important role in the development of renal injury through its vasoactive and proinflammatory activities. We investigated whether some of the effects of Ang II could be mediated through the production of macrophage migration inhibitory factor (MIF).


METHODS
Groups of rats underwent sham surgery (sham), subtotal nephrectomy (STNx), or STNx plus treatment with irbesartan. Renal tissue was examined 12 weeks postsurgery for MIF mRNA expression and leukocyte accumulation. To determine whether Ang II had a direct effect on MIF production, mRNA synthesis and protein secretion were examined in proximal tubular epithelial (NRK52E and MCT) cell lines.


RESULTS
MIF mRNA was strongly expressed in 5.4%+/- 1.1% (mean +/- SD) of cortical tubules of sham-operated rats. This was significantly up-regulated in STNx rats (44.9%+/- 22.6%) and was abrogated by administration of irbesartan (2.8%+/- 2.4%). STNx resulted in significant glomerular and interstitial accumulation of macrophages and T cells, which correlated with glomerular and tubular MIF mRNA expression, respectively. In vitro studies of tubular epithelial cells revealed that Ang II caused a twofold increase in MIF mRNA expression in NRK52E and MCT cells, which was abrogated by irbesartan. In addition, Ang II induced a rapid release of 50% of MIF protein from NRK52E cells within 20 minutes.


CONCLUSIONS
This study has demonstrated that Ang II up-regulates MIF mRNA production and MIF protein secretion by tubular epithelial cells. Ang II may promote accumulation and activation of interstitial leukocytes via induction of MIF synthesis and secretion in renal tubular epithelial cells. This may be an important mechanism by which Ang II mediates renal injury.
Rice
Edwina K
EK
Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia. edwina.rice@med.monash.edu.au
Tesch
Gregory H
GH
Cao
Zemin
Z
Cooper
Mark E
ME
Metz
Christine N
CN
Bucala
Richard
R
Atkins
Robert C
RC
Nikolic-Paterson
David J
DJ
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D000077405:Irbesartan; D007684:Kidney Tubules / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000166:cytology; D009392:Nephrectomy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013601:T-Lymphocytes / Q000166:cytology; D013777:Tetrazoles / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D008263:Macrophage Migration-Inhibitory Factors; D012333:RNA, Messenger; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D000077405:Irbesartan