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Cilastatin protects against tacrolimus-induced nephrotoxicity via anti-oxidative and anti-apoptotic properties

BACKGROUND: Cilastatin (CL) is an inhibitor of dehydropeptidase-I, which is safely used in clinical practice to prevent nephrotoxicity of antibiotics. Tacrolimus (TAC) is the most important immunosuppressant in renal transplantation, but it causes considerable nephrotoxicity. We evaluated the protec...

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Autores principales: Luo, Kang, Lim, Sun Woo, Jin, Jian, Jin, Long, Gil, Hyo Wook, Im, Dai Sig, Hwang, Hyeon Seok, Yang, Chul Woo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570925/
https://www.ncbi.nlm.nih.gov/pubmed/31200653
http://dx.doi.org/10.1186/s12882-019-1399-6
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author Luo, Kang
Lim, Sun Woo
Jin, Jian
Jin, Long
Gil, Hyo Wook
Im, Dai Sig
Hwang, Hyeon Seok
Yang, Chul Woo
author_facet Luo, Kang
Lim, Sun Woo
Jin, Jian
Jin, Long
Gil, Hyo Wook
Im, Dai Sig
Hwang, Hyeon Seok
Yang, Chul Woo
author_sort Luo, Kang
collection PubMed
description BACKGROUND: Cilastatin (CL) is an inhibitor of dehydropeptidase-I, which is safely used in clinical practice to prevent nephrotoxicity of antibiotics. Tacrolimus (TAC) is the most important immunosuppressant in renal transplantation, but it causes considerable nephrotoxicity. We evaluated the protective effects of CL against chronic TAC-induced nephropathy. METHODS: Chronic nephropathy was induced by administering TAC (1.5 mg/kg/ day, subcutaneous injection) to rats on a low-salt diet for 4 weeks. CL (75 or 150 mg/kg/day, intraperitoneal injection) was concomitantly treated with TAC. Human proximal tubular cells were exposed to TAC (50 μg/mL) with or without CL (250 μg/mL). We investigated the effects of CL on TAC-induced injury in terms of renal function, tubulointerstitial fibrosis, and inflammation. The effects of CL on oxidative stress and apoptosis were evaluated in both in vivo and in vitro models of TAC nephrotoxicity. RESULTS: CL treatment improved TAC-induced renal dysfunction and decreased renal interstitial fibrosis (reduced expression of e-cadherin and TGFβ-1) and interstitial inflammation (decreased infiltration of ED-1-positive and osteopontin-positive cells). Compared to TAC treatment alone, CL co-treatment reduced oxidative stress (serum 8-OHdG level and immunoreactivity of 8-OHdG and 4-HHE in renal tissue) and increased renal expression of anti-oxidant enzyme, manganese superoxide dismutase. CL treatment decreased apoptotic cell death (decreased TUNEL-positive cells and reduced expression of active caspase-3) in TAC-treated kidney. In vitro CL treatment prevented tubular cell death from TAC treatment and decreased number of annexin V-positive cells were observed in cilastatin-cotreated cells. CONCLUSION: CL has protective effects against chronic TAC-induced nephrotoxicity owing to its anti-oxidative and anti-apoptotic properties. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12882-019-1399-6) contains supplementary material, which is available to authorized users.
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spelling pubmed-65709252019-06-20 Cilastatin protects against tacrolimus-induced nephrotoxicity via anti-oxidative and anti-apoptotic properties Luo, Kang Lim, Sun Woo Jin, Jian Jin, Long Gil, Hyo Wook Im, Dai Sig Hwang, Hyeon Seok Yang, Chul Woo BMC Nephrol Research Article BACKGROUND: Cilastatin (CL) is an inhibitor of dehydropeptidase-I, which is safely used in clinical practice to prevent nephrotoxicity of antibiotics. Tacrolimus (TAC) is the most important immunosuppressant in renal transplantation, but it causes considerable nephrotoxicity. We evaluated the protective effects of CL against chronic TAC-induced nephropathy. METHODS: Chronic nephropathy was induced by administering TAC (1.5 mg/kg/ day, subcutaneous injection) to rats on a low-salt diet for 4 weeks. CL (75 or 150 mg/kg/day, intraperitoneal injection) was concomitantly treated with TAC. Human proximal tubular cells were exposed to TAC (50 μg/mL) with or without CL (250 μg/mL). We investigated the effects of CL on TAC-induced injury in terms of renal function, tubulointerstitial fibrosis, and inflammation. The effects of CL on oxidative stress and apoptosis were evaluated in both in vivo and in vitro models of TAC nephrotoxicity. RESULTS: CL treatment improved TAC-induced renal dysfunction and decreased renal interstitial fibrosis (reduced expression of e-cadherin and TGFβ-1) and interstitial inflammation (decreased infiltration of ED-1-positive and osteopontin-positive cells). Compared to TAC treatment alone, CL co-treatment reduced oxidative stress (serum 8-OHdG level and immunoreactivity of 8-OHdG and 4-HHE in renal tissue) and increased renal expression of anti-oxidant enzyme, manganese superoxide dismutase. CL treatment decreased apoptotic cell death (decreased TUNEL-positive cells and reduced expression of active caspase-3) in TAC-treated kidney. In vitro CL treatment prevented tubular cell death from TAC treatment and decreased number of annexin V-positive cells were observed in cilastatin-cotreated cells. CONCLUSION: CL has protective effects against chronic TAC-induced nephrotoxicity owing to its anti-oxidative and anti-apoptotic properties. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12882-019-1399-6) contains supplementary material, which is available to authorized users. BioMed Central 2019-06-14 /pmc/articles/PMC6570925/ /pubmed/31200653 http://dx.doi.org/10.1186/s12882-019-1399-6 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Luo, Kang
Lim, Sun Woo
Jin, Jian
Jin, Long
Gil, Hyo Wook
Im, Dai Sig
Hwang, Hyeon Seok
Yang, Chul Woo
Cilastatin protects against tacrolimus-induced nephrotoxicity via anti-oxidative and anti-apoptotic properties
title Cilastatin protects against tacrolimus-induced nephrotoxicity via anti-oxidative and anti-apoptotic properties
title_full Cilastatin protects against tacrolimus-induced nephrotoxicity via anti-oxidative and anti-apoptotic properties
title_fullStr Cilastatin protects against tacrolimus-induced nephrotoxicity via anti-oxidative and anti-apoptotic properties
title_full_unstemmed Cilastatin protects against tacrolimus-induced nephrotoxicity via anti-oxidative and anti-apoptotic properties
title_short Cilastatin protects against tacrolimus-induced nephrotoxicity via anti-oxidative and anti-apoptotic properties
title_sort cilastatin protects against tacrolimus-induced nephrotoxicity via anti-oxidative and anti-apoptotic properties
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570925/
https://www.ncbi.nlm.nih.gov/pubmed/31200653
http://dx.doi.org/10.1186/s12882-019-1399-6
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