Cyclosporine-mediated allograft fibrosis is associated with micro-RNA-21 through AKT signaling

Chen, Jianguo; Zmijewska, Anna A.; Zhi, Degui; Mannon, Roslyn B.

doi:10.1111/tri.12471

Cited by 29 publications

(28 citation statements)

References 61 publications

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“…miR-21-dependent targeting PTEN and Smad7 was also found to be responsible for the progression of renal fibrosis in human diabetic nephropathy [83]. In a model of cyclosporine A- (CsA-) induced renal injury, downregulation of Smad7 and increase in TGF- β 1 were independent of miR-21, but miR-21 mediated CsA nephrotoxicity via PTEN/Akt signaling pathway [84]. In patients with IgA nephropathy (IgAN) miR-21 was upregulated in both glomerular and tubular-interstitial tissues.…”

Section: Mir-21 In Renal Fibrosis and Inflammationmentioning

confidence: 99%

TGF-β1/Smads and miR-21 in Renal Fibrosis and Inflammation

Łoboda

Sobczak

Józkowicz

et al. 2016

Mediators of Inflammation

257

202

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Renal fibrosis, irrespective of its etiology, is a final common stage of almost all chronic kidney diseases. Increased apoptosis, epithelial-to-mesenchymal transition, and inflammatory cell infiltration characterize the injured kidney. On the molecular level, transforming growth factor-β1 (TGF-β1)-Smad3 signaling pathway plays a central role in fibrotic kidney disease. Recent findings indicate the prominent role of microRNAs, small noncoding RNA molecules that inhibit gene expression through the posttranscriptional repression of their target mRNAs, in different pathologic conditions, including renal pathophysiology. miR-21 was also shown to play a dynamic role in inflammatory responses and in accelerating injury responses to promote organ failure and fibrosis. Understanding the cellular and molecular bases of miR-21 involvement in the pathogenesis of kidney diseases, including inflammatory reaction, could be crucial for their early diagnosis. Moreover, the possibility of influencing miR-21 level by specific antagomirs may be considered as an approach for treatment of renal diseases.

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Section: Mir-21 In Renal Fibrosis and Inflammationmentioning

confidence: 99%

TGF-β1/Smads and miR-21 in Renal Fibrosis and Inflammation

Łoboda

Sobczak

Józkowicz

et al. 2016

Mediators of Inflammation

257

202

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“…For example, increased expression of miR-21 is associated with kidney fibrosis [11–13]. MiR-21 also has been proven to be related to the rate of kidney function decline [14] and specificly associated with cyclosporine-mediated allograft fibrosis [15] which is a hallmark of the end-stage renal disease. Also, several microRNAs, such as miR-130, miR-192 and miR-200, have been reported to have a regulatory role in kidney diseases [16, 17].…”

Section: Introductionmentioning

confidence: 99%

Cyclosporine A alters expression of renal microRNAs: New insights into calcineurin inhibitor nephrotoxicity

et al. 2017

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Calcineurin inhibitors are powerful immunosuppressants that revolutionized organ transplantation. However, non-immune effects of the calcineurin inhibitor, such as cyclosporine A (CsA), have significantly hindered their use. Specifically, nephrotoxicity, which is associated with tubulointerstitial fibrosis, inflammation, and podocyte damage, affects up to half of all transplant patients. Calcineurin is involved in many aspects of kidney development and function; therefore, mechanisms of CsA-induced nephrotoxicity are complex and not yet fully understood. MicroRNAs are short non-coding RNAs that regulate protein-coding RNA expression through post-translational repression of target messenger RNAs. MicroRNA dysregulation is known to be involved in kidney diseases including fibrosis. In this study, we compared the renal microRNA expression profiles between mice that received CsA (20 mg/kg) or vehicle daily for six weeks. The results demonstrate that CsA induces significant changes in renal microRNA expression profile. We used combined criteria of False Discovery Rate (≤0.1), fold change (≥2) and median signal strength (≥50) and identified 76 differencially expressed microRNAs. This approach identified microRNAs previously linked to renal fibrosis that includes let-7d, miR-21, miR-29, miR-30, miR-130, miR-192, and miR-200 as well as microRNAs that have not been reported to be related to nephrotoxicity or immunosuppression. Pathway analysis of microRNA/mRNA changes highlights the Wnt, TGF-β, mTOR, and VEGF pathways. The mRNA expression profiles were compared in the same samples. The change of mRNA and microRNA profiles showed close correlations. To validate that the observed microRNA and mRNA expression level changes in mice kidney tissue were directly related to CsA treatment, the expression change induced by CsA treatment of three microRNAs (miR-21, miR-186, and miR-709) and three mRNAs (BMPR1a, SMURF1 and SMAD7) were compared in HEK293 cell line. A similar trend of expression level change was induced by CsA treatment in all selected microRNAs and mRNAs in the in vitro cell model. These data provide a roadmap for future work to study the role of the known and novel candidate microRNAs in the mechanism of nephrotoxicity and their further therapeutic potential.

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“…This effect appears to be related to TLR4 downregulation by the induction of an miR, Let-7i, due to the presence of CsA. Several studies already showed that CsA can specifically induce miRs in different cell types, such as cardiomyocytes, glioma cells, and renal tubular epithelial cells [34][35][36][37]. CsA binds to cyclophilin and the cyclophilin-CsA complex will then bind to calcineurin, a protein phosphatase 2B, PP2B, and inhibit IL-2 synthesis, and thereby T-cell functions.…”

Section: Discussionmentioning

confidence: 99%

“…It was previously shown that Let-7 family members can modulate TLR4 signaling. Let-7i regulates TLR4 expression in cholangiocytes and contributes to epithelial immune responses against C. parvum infection [34]. Another study showed that the expression of Let-7i is associated with the TLR4 signal in coronary artery disease, and statins downregulate the signal via Let-7i expression in these patients [42].…”

Section: Discussionmentioning

confidence: 99%

“…Before the infection with UPEC, a group of mice untreated with CsA received an intraperitoneal injection of 2 nmol of Let-7i mimic per mouse. We checked the presence of the Let-7i mimics by quantitative PCR and FACS on microdissected MCD cells from the tubules of the injected mice, as previously shown [34]. At 24 h after infection, the bacterial load in the kidneys of mice treated with CsA was increased compared to CsA-untreated mice (Fig.…”

Section: Administration Of a Synthetic Let-7i Mimics The Deleterious mentioning

confidence: 99%

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Cyclosporine A Induces MicroRNAs Controlling Innate Immunity during Renal Bacterial Infection

Sadio

Tourneur²,

Bens³

et al. 2017

J Innate Immun

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Urinary tract infections (UTIs) mainly due to uropathogenic Escherichia coli (UPEC) are one of the most frequent complications in kidney-transplanted patients, causing significant morbidity. However, the mechanisms underlying UTI in renal grafts remain poorly understood. Here, we analysed the effects of the potent immunosuppressive agent cyclosporine A (CsA) on the activation of collecting duct cells that represent a preferential site of adhesion and translocation for UPEC. CsA induced the inhibition of lipopolysaccharide- induced activation of collecting duct cells due to the downregulation of the expression of TLR4 via the microRNA Let-7i. Using an experimental model of ascending UTI, we showed that the pretreatment of mice with CsA prior to infection induced a marked fall in cytokine production by collecting duct cells, neutrophil recruitment, and a dramatic rise of bacterial load, but not in infected TLR4-defective mice kidneys. This effect was also observed in CsA-treated infected kidneys, where the expression of Let-7i was increased. Treatment with a synthetic Let-7i mimic reproduced the effects of CsA. Conversely, pretreatment with an anti-Let-7i antagonised the effects of CsA and rescued the innate immune response of collecting duct cells against UPEC. Thus, the utilisation of an anti-Let-7i during kidney transplantation may protect CsA-treated patients from ascending bacterial infection.

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Cyclosporine-mediated allograft fibrosis is associated with micro-RNA-21 through AKT signaling

Cited by 29 publications

References 61 publications

TGF-β1/Smads and miR-21 in Renal Fibrosis and Inflammation

TGF-β1/Smads and miR-21 in Renal Fibrosis and Inflammation

Cyclosporine A alters expression of renal microRNAs: New insights into calcineurin inhibitor nephrotoxicity

Cyclosporine A Induces MicroRNAs Controlling Innate Immunity during Renal Bacterial Infection

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