Mechanisms of Cyclosporine-Induced Renal Cell Apoptosis: A Systematic Review

Xiao, Zheng; Shan, Juan; Li, Chengwen; Luo, Lei; Lu, Jun; Li, Shengfu; Long, Dan; Li, Youping

doi:10.1159/000345988

Cited by 49 publications

(41 citation statements)

References 127 publications

(60 reference statements)

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“…In patients, as well as animal models, it has been associated with renal toxicity (23), which may reflect its ability of suppress renal , an inhibitor of NF-κB activation had no effect in any studied tissue (A-E). Data are means ± SEM; n = 4.…”

Section: Resultsmentioning

confidence: 99%

Systematic study of constitutive cyclooxygenase-2 expression: Role of NF-κB and NFAT transcriptional pathways

Kirkby

Chan

Zaiss

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

142

115

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Cyclooxygenase-2 (COX-2) is an inducible enzyme that drives inflammation and is the therapeutic target for widely used nonsteroidal antiinflammatory drugs (NSAIDs). However, COX-2 is also constitutively expressed, in the absence of overt inflammation, with a specific tissue distribution that includes the kidney, gastrointestinal tract, brain, and thymus. Constitutive COX-2 expression is therapeutically important because NSAIDs cause cardiovascular and renal side effects in otherwise healthy individuals. These side effects are now of major concern globally. However, the pathways driving constitutive COX-2 expression remain poorly understood. Here we show that in the kidney and other sites, constitutive COX-2 expression is a sterile response, independent of commensal microorganisms and not associated with activity of the inflammatory transcription factor NF-κB. Instead, COX-2 expression in the kidney but not other regions colocalized with nuclear factor of activated T cells (NFAT) transcription factor activity and was sensitive to inhibition of calcineurin-dependent NFAT activation. However, calcineurin/NFAT regulation did not contribute to constitutive expression elsewhere or to inflammatory COX-2 induction at any site. These data address the mechanisms driving constitutive COX-2 and suggest that by targeting transcription it may be possible to develop antiinflammatory therapies that spare the constitutive expression necessary for normal homeostatic functions, including those important to the cardiovascular-renal system. cyclooxygenase | nonsteroidal antiinflammatory drugs | prostacyclin | cardiovascular | Vioxx C yclooxygenase (COX) converts arachidonic acid to prostanoids, which include prostaglandins (PGs), prostacyclin, and thromboxane. Prostanoids are important mediators that regulate diverse functions in the cardiovascular, gastrointestinal, urogenital, and nervous systems, as well as playing critical roles in immunity, inflammation and resolution of inflammation. There are two COX

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Section: Resultsmentioning

confidence: 99%

Systematic study of constitutive cyclooxygenase-2 expression: Role of NF-κB and NFAT transcriptional pathways

Kirkby

Chan

Zaiss

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

142

115

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“…It is known that caspase 3 is an important molecule in the signal transduction pathway of apoptosis. 30 TNF-a is one of the inducers of apoptosis 31 and functions by suppressing p53. 32 The present data show that IL-13 also suppresses caspase 3 and TNF-a in the CD4…”

Section: Discussionmentioning

confidence: 99%

Interleukin-13 interferes with activation-induced t-cell apoptosis by repressing p53 expression

Yang

Liu

et al. 2015

Cell Mol Immunol

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The etiology and the underlying mechanism of CD4 1 T-cell polarization are unclear. This study sought to investigate the mechanism by which interleukin (IL)-13 prevents the activation-induced apoptosis of CD4 1 T cells. Here we report that CD4 1T cells expressed IL-13 receptor a2 in the intestine of sensitized mice. IL-13 suppressed both the activation-induced apoptosis of CD4 1 T cells and the expression of p53 and FasL. Exposure to recombinant IL-13 inhibited activation-induced cell death (AICD) along with the expression of p53, caspase 3, and tumor necrosis factor-a in CD41 T cells. Administration of an anti-IL-13 antibody enhanced the effect of specific immunotherapy on allergic inflammation in the mouse intestine, enforced the expression of p53 in intestinal CD41 T cells, and enhanced the frequency of CD4 1 T-cell apoptosis upon challenge with specific antigens. In summary, blocking IL-13 enhances the therapeutic effect of antigen-specific immunotherapy by regulating apoptosis and thereby enforcing AICD in CD4 1 T cells.

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“…After 1 week on the low-sodium diet, the mice were assigned to either the CsA group or the control group. In the CsA group, CsA (Sigma Co., St. Louis, MO, USA) was administrated subcutaneously once per day at a dose of 30 mg/kg/day, as previously reported [11,12]. The CsA was dissolved in olive oil at a final concentration of 15 mg/mL.…”

Section: Animalsmentioning

confidence: 99%

CD44-Positive Glomerular Parietal Epithelial Cells in a Mouse Model of Calcineurin Inhibitors-Induced Nephrotoxicity

Hayashi¹,

Okamoto²,

Yamazaki³

et al. 2019

Nephron

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Background/Aims: Calcineurin inhibitors (CNIs) such as cyclosporine A (CsA) and tacrolimus are immunosuppressants that are frequently used as “key drugs” in the fields of transplantation, steroid resistance, refractory nephrotic syndrome, and autoimmune disease. However, long-term CNI use causes nephrotoxicity, the features of which are arteriolar hyalinosis, tubular atrophy, striped interstitial fibrosis, and focal segmental glomerulosclerosis (FSGS). We investigated whether FSGS in CNI-induced nephrotoxicity is associated with CD44-positive glomerular parietal epithelial cells (PECs), which play a significant role in experimental and human FSGS pathogenesis. Methods: We utilized the mouse model of CsA-induced nephrotoxicity, as well as controls. Histopathological and functional data were sequentially collected from 1 to 25 weeks after CsA injection. Glomerular expression of CD44 was immunohistochemically evaluated, as were markers for glomerular podocytes and PECs. Results: Glomerular CD44 expression occurred from 2 weeks after CsA injection and gradually increased in the CsA group. CD44-positive glomerular cells showed coexpression of claudin-1 (PEC marker) but not of synaptopodin (podocyte marker). From 20 weeks after CsA injection, the cells formed a bridge between Bowman’s capsule and the capillary tuft. These features are compatible with those of activated PECs, in which increased foot process effacement leads to bridge formation, and subsequently to an increase in glomerulosclerosis and a decrease in the expression of podocyte markers from 20 weeks. Conclusion: CD44-positive (activated) PECs reflect extremely early podocyte injury in the progression of FSGS formation and may be a good marker for early detection of CNI-induced nephrotoxicity.

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Mechanisms of Cyclosporine-Induced Renal Cell Apoptosis: A Systematic Review

Cited by 49 publications

References 127 publications

Systematic study of constitutive cyclooxygenase-2 expression: Role of NF-κB and NFAT transcriptional pathways

Systematic study of constitutive cyclooxygenase-2 expression: Role of NF-κB and NFAT transcriptional pathways

Interleukin-13 interferes with activation-induced t-cell apoptosis by repressing p53 expression

CD44-Positive Glomerular Parietal Epithelial Cells in a Mouse Model of Calcineurin Inhibitors-Induced Nephrotoxicity

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