Tacrolimus-induced nephrotoxicity in mice is associated with microRNA deregulation

Vandenbussche, C.; Hauwaert, Cynthia Van der; Dewaeles, Edmone; Franczak, Jessica; Hennino, Marie-Flore; Gnemmi, Viviane; Savary, Grégoire; Tavernier, Quentin; Nottet, Nicolas; Paquet, Agnès; Perrais, Michaël; Blum, David; Mari, Bernard; Pottier, Nicolas; Glowacki, François; Cauffiez, Christelle

doi:10.1007/s00204-018-2158-3

Cited by 20 publications

(19 citation statements)

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“…In a recent study, Sun et al suggested that the antifibrotic effect of pioglitazone, which is a type of PPARγ agonist, is connected with the modulation of the miR-21-5p/Smad-7 pathway [35]. Tacrolimus-induced nephropathy (which especially manifests as IFTA or glomerular sclerosis) was associated with upregulation of miR-21 in mice renal proximal tubular epithelial cells [36]. Other mechanisms of promoting kidney fibrosis involving miR-21 are also described in the literature [37][38][39].…”

Section: Discussionmentioning

confidence: 99%

Urinary MicroRNA-21-5p as Potential Biomarker of Interstitial Fibrosis and Tubular Atrophy (IFTA) in Kidney Transplant Recipients

et al. 2020

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Chronic renal allograft dysfunction (CAD) is a major limiting factor of long-term graft survival. The hallmarks of progressive CAD are interstitial fibrosis and tubular atrophy (IFTA). MicroRNAs are small, regulatory RNAs involved in many immunological processes. In particular, microRNA-21-5p (miR-21) is considered to be strongly associated with pathogenesis regarding tubulointerstitium. The aim of this study was to assess urinary miR-21 expression levels in the kidney transplant recipients and determine their application in the evaluation of IFTA and kidney allograft function. The expression levels of miR-21 were quantified in the urine of 31 kidney transplant recipients with biopsy-assessed IFTA (IFTA 0 + I: n = 17; IFTA II + III: n = 14) by real-time quantitative PCR. Urine samples were collected at the time of protocolar biopsies performed 1 or 2 years after kidney transplantation. MicroRNA-191-5p was used as reference gene. MiR-21 was significantly up-regulated in IFTA II + III group compared to IFTA 0 + I group (p = 0.003). MiR-21 correlated significantly with serum concentration of creatinine (r = 0.52, p = 0.003) and eGFR (r = −0.45; p = 0.01). ROC analysis determined the diagnostic value of miR-21 with an area under curve (AUC) of 0.80 (p = 0.0002), sensitivity of 0.86 and specificity of 0.71. miR-21 is associated with renal allograft dysfunction and IFTA. Therefore, it could be considered as a potential diagnostic, non-invasive biomarker for monitoring renal graft function.

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Section: Discussionmentioning

confidence: 99%

Urinary MicroRNA-21-5p as Potential Biomarker of Interstitial Fibrosis and Tubular Atrophy (IFTA) in Kidney Transplant Recipients

et al. 2020

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“…It is a multifactorial process that begins with acute local inflammation, oxidative stress, renal vasoconstriction, and ends with a chronic fibrogenic response after prolonged FK506 use. 32 Deleteriously, FK506 repeated injection affected renal biomarkers in serum and tissue homogenate ( Table 1 ). The results of this study are consistent with the previous in that FK506-induced nephrotoxicity can be characterized by increased levels of cystatin C and urea ( Figures 4 and 5 ).…”

Section: Discussionmentioning

confidence: 99%

<p>Effect of Kaempferol on Tacrolimus-Induced Nephrotoxicity and Calcineurin B1 Expression Level in Animal Model</p>

Ali¹,

Almalki²,

Alharthy³

2020

JEP

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Background The kidneys are considered one of the most susceptible organs for adverse drug effects, particularly in post-transplant conditions. Tacrolimus (FK506), a calcineurin inhibitor immunosuppressant, is an essential component in the transplantation regimen. Despite that, nephrotoxicity is a severe drawback for its chronic utilization, where oxidative stress might be implicated. Kaempferol (KMF) is a natural flavonoid that has many adaptable biological activities, including antioxidant action. Objective Exploring the KMF protective effect on FK506-induced nephrotoxicity and the underlying role of calcineurin B1. Methods Twenty-four male albino-Wistar rats were randomly divided into three equal groups. The control group received solvents: propylene glycol, i.p. and 0.5% carboxymethyl cellulose, PO; FK506 group was injected with FK506 (0.6 mg/kg, i.p.), and FK506+KMF group was given FK506 (0.6 mg/kg, i.p.) and KMF (10 mg/kg, PO). The treatment regimen for all groups was once daily for 30 days. ELISA technique applied for measuring FK506 trough level and nephrotoxicity biomarkers in serum (cystatin C and urea) on days 15 and 30, and in kidney tissue homogenate (MDA and calcineurin B1) on day 30. Results In FK506-treated rats, the FK506 trough level was 7.84 ± 1.31 ug/l on day 15 and 9.54 ± 1.45 ug/l on day 30. FK506 use has significantly ( P <0.01) increased biomarkers levels of cystatin C (325% and 477%), urea (177% and 245%), MDA (1253%), except calcineurin B1 that has decreased (97%). The KMF combination has resulted in a significant reduction in the FK506 trough level by day 30 (6.79 ± 1.35 ug/l, P <0.01). KMF has significantly ameliorated the levels of cystatin C (46% and 73%, P <0.001), urea (38% and 68%, P< 0.001), MDA (75%, P <0.001), and calcineurin B1 (1833%, P <0.05). Conclusion Oxidative stress and calcineurin B1 are contributing factors in FK506-induced nephrotoxicity. Hence, inhibition of calcineurin enzyme is not limited to the immune cells. KMF could be a novel nephroprotective antioxidant.

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“…We downloaded the following four gene expression datasets from the Gene Expression Omnibus (GEO) database 1 : (1) GSE12682 (Si et al, 2009) comparing human kidney tissue between 29 healthy controls and 23 CKD samples, measured by the Affymetrix Human Genome U133A 2.0 Array (Affymetrix; Thermo Fisher Scientific, Waltham, MA, United States); (2) GSE12683 (Si et al, 2009) comparing Balb/c mouse kidney tissue between 10 healthy controls and 10 samples with AKI, measured by Affymetrix Mouse Genome 430A 2.0 Array; (3) GSE102513 (Vandenbussche et al, 2018) comparing CD-1 mouse kidney tissue between four healthy controls and four samples CKD induced by Tacrolimus (1 mg/kg/day for 28 days), measured by the Agilent-028005 SurePrint G3 Mouse GE 8x60K Microarray; and (4) GSE85957 (Pavkovic et al, 2014) comparing Rattus norvegicus (brown rat) kidney tissue samples between 19 healthy controls and 38 rats with kidney disease induced with 1 or 3 mg/kg cisplatin. In this last dataset, tissue was collected on days 3, 5, 8, and 26, and gene expression was measured using the Rat Genome 230 2.0 Array.…”

Section: Prediction Of Genes Associated With Aki or Ckdmentioning

confidence: 99%

Regulatory T Cells as a Novel Candidate for Cell-Based Therapy in Kidney Disease

Zhang

Chen

et al. 2020

Front. Physiol.

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Kidney disease is a significant health concern worldwide. Ineffective treatment can lead to disastrous consequences, such as organ failure and death. Research has turned to cell-based therapy, but has yet to produce an effective and reliable treatment for kidney disease. To address this problem, we examined four datasets of gene expression profiles from diseased and healthy kidney tissue in humans, mice, and rats. Differentially expressed genes (DEGs) were screened and subjected to enrichment analyses. Upregulated genes in diseased kidney tissue were significantly enriched in pathways associated with regulatory T cells (Tregs). Analysis with the xCell tool showed that Tregs were generally increased in diseased kidney tissue in all species. To validate these results in vivo, kidneys were removed from mice with Adriamycin-induced nephropathy, and histology confirmed increase of Tregs. Furthermore, Tregs were adoptively transferred from healthy mice into mice with kidney injury, restoring normal structure to the damaged kidneys. Treg cells that were co-cultured with M2c macrophages exhibited up-regulation of chemokine receptors CCR2, CCR5, CCR7, CD62L, and CX3CR1. This may be the mechanism by which M2c cells enhance the migration of Tregs to the site of inflammation. We propose that Tregs may be an effective, novel candidate for cell-based therapy in pre-clinical kidney injury models.

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Tacrolimus-induced nephrotoxicity in mice is associated with microRNA deregulation

Cited by 20 publications

References 45 publications

Urinary MicroRNA-21-5p as Potential Biomarker of Interstitial Fibrosis and Tubular Atrophy (IFTA) in Kidney Transplant Recipients

Urinary MicroRNA-21-5p as Potential Biomarker of Interstitial Fibrosis and Tubular Atrophy (IFTA) in Kidney Transplant Recipients

<p>Effect of Kaempferol on Tacrolimus-Induced Nephrotoxicity and Calcineurin B1 Expression Level in Animal Model</p>

Regulatory T Cells as a Novel Candidate for Cell-Based Therapy in Kidney Disease

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