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

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. Electronic supplementary material The online version of this article (10.1186/s12882-019-1399-6) contains supplementary material, which is available to authorized users.

Astragaloside IV Alleviates Tacrolimus-Induced Chronic Nephrotoxicity via p62-Keap1-Nrf2 Pathway

“…It is well documented that the transcriptional activation of antioxidant proteins is dominantly regulated by the redox-sensitive transcription factor Nrf2. Although antioxidant stress has been proved to be effective in ameliorating TIN ( Lim et al, 2017 ; Lim et al, 2019a ; Luo et al, 2019 ), the role of Nrf2 in TIN has rarely been researched. However, we failed to observed that tacrolimus impacted the expression of Nrf2 ( p > 0.05).…”

“…Consequently, the excessive ROS causes irreversible damage of the renal architecture, which is mainly manifested as striped interstitial fibrosis ( Lusco et al, 2017 ). Therefore, anti-oxidative stress therapy may be a potential candidate for TIN ( Lim et al, 2017 ; Luo et al, 2019 ).…”

Renoprotective Effects of Alpha-1 Antitrypsin against Tacrolimus-Induced Renal Injury

“…However, chronic TAC nephropathy caused by the long-term use of TAC is a major cause of late graft failure in KT recipients [ 16 ]. Therefore, researchers are interested in reducing nephrotoxicity, and several trials have been conducted to inhibit the various pathophysiologic pathways involved in TAC-induced nephrotoxicity [ 3 , 17 , 18 ]. We have focused on the effects of AAT on renal fibrosis, inflammation, and apoptosis.…”

TUNEL Assay: A Powerful Tool for Kidney Injury Evaluation

“…In lupus nephritis and membranoproliferative glomerulonephritis, TUNEL-positivity was seen primarily in the glomeruli [ 62 , 108 , 109 ]. On the other hand, drug safety studies of cisplatin [ 110 ], chloroquine [ 45 ], doxorubicin [ 67 ], finasteride [ 23 ], tacrolimus [ 111 ], and levetiracetam [ 24 ] observed mostly tubular damage. Likewise, the continued acute injury identified by tubular TUNEL-positive cells were described in studies of uric acid nephropathy [ 112 ], methionine deficiency [ 48 ], exposure to environmental toxins microcystin-LR [ 50 ] and cadmium [ 113 ], and in association with calcium-oxalate induced kidney stones [ 114 ] and calcifying nanoparticles [ 115 ].…”