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Cilastatin protects against tacrolimus-induced nephrotoxicity via anti-oxidative and anti-apoptotic properties.
BMC Nephrol 2019; 20(1):221BN

Abstract

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.

Authors+Show Affiliations

Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The College of Medicine, The Catholic University of Korea, Seoul, South Korea. Department of Nephrology, Yanbian University Hospital, Yanbian, China.Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The College of Medicine, The Catholic University of Korea, Seoul, South Korea.Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The College of Medicine, The Catholic University of Korea, Seoul, South Korea. Department of Nephrology, Yanbian University Hospital, Yanbian, China.Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The College of Medicine, The Catholic University of Korea, Seoul, South Korea.Division of Nephrology, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, South Korea.Department of Chemistry, College of Natural Sciences, Soonchunhyang University, Asan, South Korea. SH Company, Asan, Chungnam, South Korea.Division of Nephrology, Department of Internal Medicine, College of Medicine, Kyung Hee University, Seoul, South Korea. hwanghsne@gmail.com.Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, The College of Medicine, The Catholic University of Korea, Seoul, South Korea. yangch@catholic.ac.kr. Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea. yangch@catholic.ac.kr.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31200653

Citation

Luo, Kang, et al. "Cilastatin Protects Against Tacrolimus-induced Nephrotoxicity Via Anti-oxidative and Anti-apoptotic Properties." BMC Nephrology, vol. 20, no. 1, 2019, p. 221.
Luo K, Lim SW, Jin J, et al. Cilastatin protects against tacrolimus-induced nephrotoxicity via anti-oxidative and anti-apoptotic properties. BMC Nephrol. 2019;20(1):221.
Luo, K., Lim, S. W., Jin, J., Jin, L., Gil, H. W., Im, D. S., ... Yang, C. W. (2019). Cilastatin protects against tacrolimus-induced nephrotoxicity via anti-oxidative and anti-apoptotic properties. BMC Nephrology, 20(1), p. 221. doi:10.1186/s12882-019-1399-6.
Luo K, et al. Cilastatin Protects Against Tacrolimus-induced Nephrotoxicity Via Anti-oxidative and Anti-apoptotic Properties. BMC Nephrol. 2019 Jun 14;20(1):221. PubMed PMID: 31200653.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cilastatin protects against tacrolimus-induced nephrotoxicity via anti-oxidative and anti-apoptotic properties. AU - Luo,Kang, AU - Lim,Sun Woo, AU - Jin,Jian, AU - Jin,Long, AU - Gil,Hyo Wook, AU - Im,Dai Sig, AU - Hwang,Hyeon Seok, AU - Yang,Chul Woo, Y1 - 2019/06/14/ PY - 2018/06/26/received PY - 2019/05/28/accepted PY - 2019/6/16/entrez PY - 2019/6/16/pubmed PY - 2019/6/16/medline KW - Cilastatin KW - Nephrotoxicity KW - Tacrolimus SP - 221 EP - 221 JF - BMC nephrology JO - BMC Nephrol VL - 20 IS - 1 N2 - 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. SN - 1471-2369 UR - https://www.unboundmedicine.com/medline/citation/31200653/Cilastatin_protects_against_tacrolimus-induced_nephrotoxicity_via_anti-oxidative_and_anti-apoptotic_properties L2 - https://www.biomedcentral.com/1471-2369/20/221 DB - PRIME DP - Unbound Medicine ER -