The role of macrophage in the pathogenesis of chronic cyclosporine-induced nephropathy

Ghee, Jung Yeon; Han, Dong He; Song, Ho Kyung; Kim, Wan Young; Kim, Su Hyun; Yoon, Hye Eun; Choi, Bum Soon; Kim, Yong Soo; Kim, Jin; Yang, Chul Woo

doi:10.1093/ndt/gfn388

Cited by 36 publications

(27 citation statements)

References 44 publications

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“…Cyclosporine nephrotoxicity is, in part, caused by oxidative stress, and urinary 8-hydroxydeoxygu anosine levels are increased by cyclosporine. [9][10][11] This is consistent with the present finding that rCoQ10, a strong antioxidant, may be protective against the nephrotoxic adverse effects of cyclosporine (Table 1). Several previous studies had suggested that cyclosporine nephrotoxicity may be improved or prevented by antioxidants.…”

Section: Discussionsupporting

confidence: 92%

Effect of Reduced Form of Coenzyme Q10 on Cyclosporine Nephrotoxicity

Sato

Ishikawa²,

Homma³

2012

Exp Clin Transplant

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Objectives: Cyclosporine, a potent immunosuppressant, has nephrotoxic adverse effects that may be mediated by oxidative stress. The reduced form of coenzyme Q10 has antioxidant effects. The aim of the present study was to evaluate the effect of the reduced form of coenzyme Q10 on cyclosporine nephrotoxicity. Materials and Methods: Six-week-old male Wistar rats were divided into 3 groups (10 animals each). Group 1 (control) received olive oil only. Group 2 received cyclosporine (30 mg/kg/d, which is an experimentally nephrotoxic dose). Group 3 received cyclosporine (30 mg/kg/d) and the reduced form of coenzyme Q10 (600 mg/kg/d). The cyclosporine and the reduced form of coenzyme Q10 were given orally for 4 weeks. Daily urinary albumin excretion, serum creatinine level, and urinary 8-hydroxydeoxyguanosine level were measured, and renal tissue was evaluated by immunohis tochemistry. Results: In rats treated with cyclosporine and the reduced form of coenzyme Q10 (group 3), there were significantly less abnormalities in mean urinary albumin excretion (group 1: 2.8 ± 0.5; group 2: 41 ± 7; group 3: 21 ± 4 µg/d), serum creatinine (group 1: 1.0 ± 0.2; group 2: 1.8 ± 0.4; group 3: 1.4 ± 0.3 mg/dL), and urine 8-hydroxydeoxyguanosine levels (group 1: 7 ± 3; group 2: 10 ± 3; group 3: 7 ± 1 mg/mL creatinine) than rats treated with cyclosporine alone (group 2). There were 8-hydroxydeoxyguanosine deposits seen in the proximal tubular cells of group 2 that were not present in rats treated with the reduced form of coenzyme Q10 (group 3). Conclusions: The reduced form of coenzyme Q10 may prevent or minimize cyclosporine nephrotoxicity by an antioxidant effect.

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Section: Discussionsupporting

confidence: 92%

Effect of Reduced Form of Coenzyme Q10 on Cyclosporine Nephrotoxicity

Sato

Ishikawa²,

Homma³

2012

Exp Clin Transplant

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“…Practically, depletion of macrophages using liposome-encapsulated clodronate significantly decreased CsA-induced renal dysfunction and fibrosis. 23 Therefore, we investigated whether DPP IV inhibition affects TAC-induced macrophage infiltration and inflammatory factors. Many studies have demonstrated that DPP IV inhibitors inhibit the production of inflammatory cytokines and the activation of the nuclear factor-κB, suggesting that it has an anti-inflammatory effect.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of dipeptidyl peptidase IV protects tacrolimus-induced kidney injury

Lim

Jin

Piao

et al. 2015

Laboratory Investigation

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Accumulating evidence shows that a gut-released hormone, the glucagon-like peptide-1 (GLP-1), has not only a glucoselowering effect but also a renoprotective effect against kidney injury. In this study, we investigated whether a dipeptidyl peptidase (DPP) IV inhibitor has a protective effect against tacrolimus-induced renal injury. Rats were treated with tacrolimus (1.5 mg/kg, subcutaneously) and the DPP IV inhibitor MK0626 (10 or 20 mg/kg, oral gavage) for 4 weeks. MK0626 treatment attenuated tacrolimus-induced renal dysfunction, tubulointerstitial fibrosis, and arteriolopathy. Moreover, these improvements were accompanied by a reduction in oxidative stress and apoptosis. MK0626 treatment increased the blood level of GLP-1 and the level of its receptor in tissue sections but did not alter the levels of other DPP IV substrates, such as neuropeptide Y and the stromal cell-derived factor-1. These data suggest that DPP IV inhibition has an important role in the renoprotection against tacrolimus-induced nephrotoxicity via antioxidative and antiapoptotic effects and preservation of the GLP-1 system.

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“…We previously clearly demonstrated that depletion of macrophages, the major infiltrating inflammatory cell type in chronic CsA nephropathy, using liposome-encapsulated clodronate, decreased CsA-induced inflammation, fibrosis, apoptotic cell death and oxidative injury [14]. Therefore, we investigated whether KRG treatment affects CsA-induced macrophage infiltration and inflammatory factors.…”

Section: Discussionmentioning

confidence: 99%

“…The high level of oxidative stress induced by chronic CsA administration causes structural and functional kidney impairment because short- and long-term CsA treatment induces free radical species in the kidney, causing apoptotic and autophagic cell death [1,12,14]. In this study, we found that the expression of the oxidative stress marker, 8-OHdG, was increased in the 24-hour urine and renal tubules and in the culture media of CsA-treated cells, but that co-treatment with KRG decreased these parameters.…”

Section: Discussionmentioning

confidence: 99%

Ginseng Treatment Attenuates Chronic Cyclosporine Nephropathy via Reducing Oxidative Stress in an Experimental Mouse Model

Doh¹,

Lim²,

Piao³

et al. 2013

Am J Nephrol

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Background: This study was performed to investigate whether ginseng extract has a protective effect in an experimental mouse model of chronic cyclosporine (CsA) nephropathy. Methods: Mice were treated with CsA (30 mg/kg/day, subcutaneously) with or without Korean red ginseng extract (KRG) (0.2, 0.4 g/kg/day, orally) on a 0.01% salt diet for 4 weeks. The effect of KRG on CsA-induced renal injury was evaluated by assessing renal function and pathology, mediators of inflammation, tubulointerstitial fibrosis and apoptotic cell death. Using an in vitro model, we also examined the effect of KRG on CsA-treated proximal tubular cells (HK-2). Oxidative stress was measured by assessing 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels in 24-hour urine, tissue sections, and culture media. Results: Four weeks of CsA treatment caused renal dysfunction, typical pathologic lesions and apoptotic cell death. KRG treatment reduced serum creatinine and blood urea nitrogen and histopathology and increased creatinine clearance. Proinflammatory and profibrotic molecules such as induced nitric oxide synthase, cytokines, transforming growth factor (TGF)-β1 and TGF-β1-inducible gene h3 and apoptotic cell death, also decreased with KRG treatment. Consistent with these results, in vitro studies showed that addition of KRG protected against CsA-induced morphological changes, cytotoxicity, inflammation, and apoptotic cell death as demonstrated by annexin V binding. These changes were accompanied by decrease in the level of 8-OHdG in urine and culture supernatant after KRG treatment. Conclusion: The results of our in vivo and in vitro studies demonstrate that KRG has a protective effect in CsA-induced renal injury via reducing oxidative stress.

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The role of macrophage in the pathogenesis of chronic cyclosporine-induced nephropathy

Abstract: Thus, infiltrating macrophages were involved in both nonimmunologic and immunologic injury and led to apoptotic cell death in this rat model of chronic CsA nephropathy.

Cited by 36 publications

References 44 publications

Effect of Reduced Form of Coenzyme Q10 on Cyclosporine Nephrotoxicity

Effect of Reduced Form of Coenzyme Q10 on Cyclosporine Nephrotoxicity

Inhibition of dipeptidyl peptidase IV protects tacrolimus-induced kidney injury

Ginseng Treatment Attenuates Chronic Cyclosporine Nephropathy via Reducing Oxidative Stress in an Experimental Mouse Model

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