Inbibition of Liver, Kidney, and Intestine Regeneration by Rapamycin

Francavilla, A.; Starzl, Thomas E.; Scotti, C.; Carrieri, G.; Azzarone, Alessandro; Zeng, Qihua; Porter, Kenneth Wiggins; Schreiber, S. L.

doi:10.1097/00007890-199202010-00045

Cited by 32 publications

(6 citation statements)

References 20 publications

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“…In the present study, we found that EVR delayed liver regeneration. This result is consistent with that reported for sirolimus 27,28 . Toso et al reported that introduction of sirolimus immediately after LDLT inhibited hepatocyte proliferation 29 .…”

Section: Discussionsupporting

confidence: 91%

“…This result is consistent with that reported for sirolimus. 27,28 Toso et al reported that introduction of sirolimus immediately after LDLT inhibited hepatocyte proliferation. 29 Ideally, liver regeneration should be evaluated in the absence of liver damage (e.g., infection or rejection) because liver weight and Ki-67 can be affected by liver damage.…”

Section: Discussionmentioning

confidence: 99%

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Impact of very early introduction of everolimus on liver regeneration after partial liver transplantation in rats

Hirata

Yagi

Ito

et al. 2023

J Hepato Biliary Pancreat

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Background/Purpose This experimental study in rats aimed to investigate the impact of very early introduction (within 3 h) of everolimus (EVR) + reduced‐tacrolimus (TAC) after partial liver transplantation (LT) on liver regeneration, rejection, and survival. Methods Based on appropriate dose of EVR + reduced‐TAC in 70% hepatectomy (Experiment 1), allogeneic 30% partial LT (Experiment 2) and whole LT (Experiment 3) were performed. Results After partial LT in EVR + reduced‐TAC therapy, restoration of liver graft weight (to that of the whole liver) was delayed compared with standard dose TAC monotherapy (standard‐TAC) on day 3 (59.3% vs. 72.9%; p < .001) and 14 (88.1% vs. 95.5%; p = .01). Survival was 75%, which was not as high as the value of 100% observed for standard‐TAC, because neither infection nor rejection could be prevented. By contrast, survival after whole LT was 100% as neither infection nor rejection occurred. Conclusions The very early introduction of EVR + reduced‐TAC after partial LT delayed liver regeneration, and made it difficult to manage the dose required to suppress both infection and rejection. On the other hand, EVR + reduced‐TAC could be introduced safely very early after whole LT.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Impact of very early introduction of everolimus on liver regeneration after partial liver transplantation in rats

Hirata

Yagi

Ito

et al. 2023

J Hepato Biliary Pancreat

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“…Rapamycin is the canonical inhibitor of mTORC1 and has been used extensively for studying mTORC1 function in various tissues. In the intestine, systemic administration of rapamycin has been shown to reduce intestinal surface area in rabbits, 9 disrupt intestine regeneration in rats, 10 cause diarrhea in human beings, 11 and inhibit intestinal regeneration in acute inflammatory bowel disease. 12 Repression of mTORC1 in Paneth cells provides a niche for enhancing intestinal stem cell proliferation while keeping rates of proliferation low in transient amplifying cells.…”

mentioning

confidence: 99%

Intestinal Epithelial-Specific mTORC1 Activation Enhances Intestinal Adaptation After Small Bowel Resection

Barron

Sun

Aladegbami

et al. 2017

Cellular and Molecular Gastroenterology and Hepatology

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Background & AimsIntestinal adaptation is a compensatory response to the massive loss of small intestine after surgical resection. We investigated the role of intestinal epithelial cell–specific mammalian target of rapamycin complex 1 (i-mTORC1) in intestinal adaptation after massive small bowel resection (SBR).MethodsWe performed 50% proximal SBR on mice to study adaptation. To manipulate i-mTORC1 activity, Villin-CreER transgenic mice were crossed with tuberous sclerosis complex (TSC)1flox/flox or Raptorflox/flox mice to inducibly activate or inactivate i-mTORC1 activity with tamoxifen. Western blot was used to confirm the activity of mTORC1. Crypt depth and villus height were measured to score adaptation. Immunohistochemistry was used to investigate differentiation and rates of crypt proliferation.ResultsAfter SBR, mice treated with systemic rapamycin showed diminished structural adaptation, blunted crypt cell proliferation, and significant body weight loss. Activating i-mTORC1 via TSC1 deletion induced larger hyperproliferative crypts and disorganized Paneth cells without a significant change in villus height. After SBR, ablating TSC1 in intestinal epithelium induced a robust villus growth with much stronger crypt cell proliferation, but similar body weight recovery. Acute inactivation of i-mTORC1 through deletion of Raptor did not change crypt cell proliferation or mucosa structure, but significantly reduced lysozyme/matrix metalloproteinase-7–positive Paneth cell and goblet cell numbers, with increased enteroendocrine cells. Surprisingly, ablation of intestinal epithelial cell–specific Raptor after SBR did not affect adaptation or crypt proliferation, but dramatically reduced body weight recovery after surgery.ConclusionsSystemic, but not intestinal-specific, mTORC1 is important for normal adaptation responses to SBR. Although not required, forced enterocyte mTORC1 signaling after resection causes an enhanced adaptive response.

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“…The mTOR pathway, particularly mTORC1, helps to maintain the structure of the mammalian intestinal mucosa 8 and is important in stem cell self-renewal 9 . Inhibition of mTOR by rapamycin has been shown to disrupt intestinal growth and regeneration in healthy animals 4, 10 .…”

Section: Introductionmentioning

confidence: 99%

Rapamycin Inhibition of mTOR Reduces Levels of the Na+/H+ Exchanger 3 in Intestines of Mice and Humans, Leading to Diarrhea

et al. 2015

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Background & Aims The immunosuppressant rapamycin frequently causes non-infectious diarrhea in recipients of organ transplants. We investigated the mechanisms of this process. Methods We performed a retrospective analysis of renal transplant recipients treated with rapamycin from 2003 through 2010 at Albany Medical College, collecting data on serum levels of rapamycin. Levels of the Na+/H+ exchanger 3 (NHE3) were measured in human ileal biopsies from patients who did and did not receive rapamycin (controls), in ileum tissues from rats or mice given rapamycin, and in mice with intestine-specific disruption of Mtor (mTORf/f:Villin-cre mice) or Atg7 (Atg7flox/flox; Villin-Cre). Exchange activity and intestinal water absorption were measured using a pH-sensitive dye and small intestine perfusion, respectively. Results Episodes of non-infectious diarrhea occurred in organ recipients following increases in serum levels of rapamycin. Expression of NHE3 was reduced in the ileal brush border of patients with diarrhea. In rats and mice, continuous administration of low doses of rapamycin reduced levels of NHE3 in intestinal tissues; this effect was not observed in mice with intestinal deletion of ATG7, indicating that autophagy is required for the reduction. Administration of single high doses of rapamycin to mice, to model the spikes in rapamycin levels that occur in patients with severe diarrheal episodes, resulted in reduced phosphorylation of S6 and AKT in ileal tissues, indicating inhibition of the mTOR complex (mTORC1 and mTORC2). Intestines of mice with intestine-specific deletion of mTOR were dilated and contained large amount of liquid stools; they also had reduced levels of total NHE3 and NHERF1, compared with control mice. We observed a significant reduction in Na+/H+ exchange activity in ileum tissues from these mice. Conclusions Rapamycin inhibition of mTOR reduces levels of NHE3 and Na+/H+ exchange activity in intestinal tissues of patients and rodents. This process appears to require the autophagic activity mediated by ATG7. Loss of mTOR regulation of NHE3 could mediate the development of diarrhea in patients undergoing rapamycin therapy.

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Inbibition of Liver, Kidney, and Intestine Regeneration by Rapamycin

Cited by 32 publications

References 20 publications

Impact of very early introduction of everolimus on liver regeneration after partial liver transplantation in rats

Impact of very early introduction of everolimus on liver regeneration after partial liver transplantation in rats

Intestinal Epithelial-Specific mTORC1 Activation Enhances Intestinal Adaptation After Small Bowel Resection

Rapamycin Inhibition of mTOR Reduces Levels of the Na+/H+ Exchanger 3 in Intestines of Mice and Humans, Leading to Diarrhea

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