The role of angiotensin II type 1a receptor on intestinal epithelial cells following small bowel resection in a mouse model.
OBJECTIVE
We have previously shown that inhibition of angiotensin converting enzyme (ACE) significantly reduced intestinal epithelial cell (EC) apoptosis and improved morphometric intestinal adaptation in a mouse model of massive small-bowel resection (SBR). This study attempted to further examine the downstream signaling factors in this system by blocking the action of angiotensin II (ATII), hypothesizing that this would lead to similar improvement of intestinal adaptation after SBR.


METHODS
Two groups of mice (C57BL/6J) underwent either a 60% mid-intestinal resection (SBR group) or a transection/re-anastomosis (Sham group). Because real-time PCR studies showed that only ATII receptor type 1a (ATII-1a) expression was significantly increased after SBR, compared to SHAM mice, we decided to use the specific ATII-1a receptor antagonist Losartan to block this signaling pathway. An additional two groups of mice received daily i.p. injections of Losartan (SBR + Losartan and Sham + Losartan group). At 7 days, the adaptive response was assessed in the remnant gut including villus height, crypt depth, EC apoptosis (TUNEL staining) and proliferation (BrdU incorporation). The apoptotic and proliferation signaling pathways were addressed by analysis of EC mRNA expression.


RESULTS
SBR (with and without Losartan) led to a significant increase in villus height and crypt depth. Losartan treatment did not significantly change EC proliferation, but did significantly reduce EC apoptosis rates as compared to the non-treated SBR group. Losartan treatment was associated with a significant reduction of the bax-to-bcl-2 ratio and TNF-alpha expression after SBR compared to non-treated groups. Interestingly, Losartan-treated groups showed a tremendous increase in proliferation of signaling factors EGFR, KGFR and IL7R, which may indicate an expanded potential for further intestinal adaptation also beyond 7 days after SBR.


CONCLUSIONS
This study showed that the ATII-1a receptor may be of crucial importance for the modulation of intestinal EC apoptosis, and for regulating the post-resectional EC adaptive response.
Koga
Hiroyuki
H
Section of Pediatric Surgery, Department of Surgery, C.S Mott Children's Hospital F3970, University of Michigan Medical School, Ann Arbor, MI 48109-0245, USA.
Yang
Hua
H
Haxhija
Emir Q
EQ
Teitelbaum
Daniel H
DH
D000222:Adaptation, Physiological / Q000187:drug effects; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004847:Epithelial Cells / Q000502:physiology*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000502:physiology; D007421:Intestine, Small / Q000187:drug effects* / Q000502:physiology* / Q000601:surgery; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology*; D015398:Signal Transduction
D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D019808:Losartan