The Protective Effect of Febuxostat on Chronic Tacrolimus-Induced Nephrotoxicity in Rats

Kim, Hyun Seon; Lim, Sun Woo; Jin, Long; Jin, Jian; Chung, Byung Ha; Yang, Chul Woo

doi:10.1159/000449289

Cited by 24 publications

(15 citation statements)

References 22 publications

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“…Apoptosis is a process of programmed cell death; unlike necrosis, apoptosis does not involve inflammation. TAC induces dose- and time-dependent renal cell apoptosis, and apoptosis plays an important role in TAC-induced renal injury [ 44 , 45 , 46 ]. We also confirmed the antiapoptotic effect of AAT aside from antifibrotic and anti-inflammatory effect.…”

Section: Discussionmentioning

confidence: 99%

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

Lim

et al. 2020

IJMS

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The protective effects of alpha-1 antitrypsin (AAT) in tacrolimus (TAC)-induced renal injury was evaluated in a rat model. The TAC group rats were subcutaneously injected with 2 mg/kg TAC every day for four weeks. The TAC with AAT group was cotreated with daily subcutaneous injections of TAC and intraperitoneal injections of AAT (80 mg/kg) for four weeks. The effects of AAT on TAC-induced renal injury were evaluated using serum biochemistry, histopathology, and Western blotting. The TAC injection significantly increased renal interstitial fibrosis, inflammation, and apoptosis as compared to the control treatment. The histopathological examination showed that cotreatment of TAC and AAT attenuated interstitial fibrosis (collagen, fibronectin, and α-SMA staining), and α-SMA expression in Western blotting was also decreased. Immunohistochemical staining for inflammation (osteopontin and ED-1 staining) revealed improved interstitial inflammation in the TAC with AAT group compared to that in the TAC group. The TAC treatment increased renal apoptosis compared to the control treatment, based on the results of increased immunohistochemical staining of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), increased caspase-3 activity, and lower Bcl-2 to Bad expression ratio. However, AAT cotreatment significantly changed these markers and consequently showed decreased apoptosis. AAT protects against TAC-induced renal injury via antifibrotic, anti-inflammatory, and antiapoptotic effects.

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Section: Discussionmentioning

confidence: 99%

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

Lim

et al. 2020

IJMS

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“…61 Experimental studies also confirmed a role of urate in animal models of diabetic kidney disease, calcineurin inhibitor nephrotoxicity, and acute kidney injury (AKI) (Table 1). 43,54,55,59,[62][63][64][66][67][68][69][70][71][72][73][74][75][76] Although many effects of urate appear to be mediated by its intracellular action, kidney injury in humans can occur with hyperuricosuria, especially in the setting of urate crystalluria and acidic urinary pH. Soluble urate and urate crystals activate inflammasomes, causing local inflammation and tubular injury.…”

Section: Models Of Hypertension and Kidney Injurymentioning

confidence: 99%

Hyperuricemia, Acute and Chronic Kidney Disease, Hypertension, and Cardiovascular Disease: Report of a Scientific Workshop Organized by the National Kidney Foundation

Johnson

Bakris

Borghi

et al. 2018

American Journal of Kidney Diseases

475

307

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Urate is a cause of gout, kidney stones, and acute kidney injury from tumor lysis syndrome, but its relationship to kidney disease, cardiovascular disease, and diabetes remains controversial. A scientific workshop organized by the National Kidney Foundation was held in September 2016 to review current evidence. Cell culture studies and animal models suggest that elevated serum urate concentrations can contribute to kidney disease, hypertension, and metabolic syndrome. Epidemiologic evidence also supports elevated serum urate concentrations as a risk factor for the development of kidney disease, hypertension, and diabetes, but differences in methodologies and inpacts on serum urate concentrations by even subtle changes in kidney function render conclusions uncertain. Mendelian randomization studies generally do not support a causal role of serum urate in kidney disease, hypertension, or diabetes, although interpretation is complicated by nonhomogeneous populations, a failure to consider environmental interactions, and a lack of understanding of how the genetic polymorphisms affect biological mechanisms related to urate. Although several small clinical trials suggest benefits of urate-lowering therapies on kidney function, blood pressure, and insulin resistance, others have been negative, with many trials having design limitations and insufficient power. Thus, whether uric acid has a causal role in kidney and cardiovascular diseases requires further study.

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“…Inflammation is reported to be involved in the development and amplification of calcineurin inhibitor (CNI)-induced fibrosis [17]. In previous studies, we demonstrated that TAC treatment induces the infiltration of inflammatory cells and the production of proinflammatory cytokines [18, 19]. Therefore, we investigated whether CL affects TAC-induced macrophage infiltration and inflammatory factors.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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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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The Protective Effect of Febuxostat on Chronic Tacrolimus-Induced Nephrotoxicity in Rats

Cited by 24 publications

References 22 publications

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

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

Hyperuricemia, Acute and Chronic Kidney Disease, Hypertension, and Cardiovascular Disease: Report of a Scientific Workshop Organized by the National Kidney Foundation

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

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