Cyclosporine A–Induced Oxidative Stress in Human Renal Mesangial Cells: A Role for ERK 1/2 MAPK Signaling

Abstract

Cyclosporine A (CsA) is a potent immunosuppressant used to prevent organ transplant rejection and in the treatment of autoimmune diseases. However, chronic CsA nephropathy is the major limiting factor to its widespread use. The exact mechanisms of CsA-induced renal damage remain to be fully elucidated. The objective of the current research was to examine whether CsA treatment induced any glomerular mesangial cell alterations. In this research goal, human mesangial cells (HMCs) were treated with CsA for various time points. CsA caused an increase in the production of reactive oxygen species (ROS). Microarray analysis of mesangial cells treated with CsA also indicated 282 dysregulated genes. Bioinformatic analysis of these 282 genes indicated enriched apoptotic oxidative stress, mitogen-activated protein kinase (MAPK), and transforming growth factor-β signaling in response to CsA treatment. The focus of this study was directed on oxidative stress and MAPK signaling as potential novel mechanisms of CsA nephrotoxicity. One key contributor to oxidative stress, thioredoxin interacting protein, was significantly upregulated following CsA treatment. Inhibition of the MAPK pathway resulted in attenuation of the CsA-induced mesangial cell alterations. These findings suggest a major role for ROS, oxidative stress, and MAPK signaling in promoting CsA-induced glomerular dysfunction and subsequent nephrotoxicity.

Lovastatin attenuates effects of cyclosporine A on tight junctions and apoptosis in cultured cortical collecting duct principal cells

“…A high concentration of CsA, but not lovastatin, elevates ROS levels in mpkCCD c14 cells via activation of NADPH oxidase. Recent studies (9,31) have suggested that CsA elevates ROS in mesangial cells and induces apoptosis in renal epithelial LLC-PK1 cells. To examine whether a high concentration of CsA elevates ROS in distal tubular cells, mpkCCD c14 cells were stained with a ROS probe.…”

Nephroprotective and antioxidant effect of aqueous leaf extract of Costus Afer Ker gawl on cyclosporin-a (Csa) induced nephrotoxicity

“…Cyclosporine A (CsA) is a potent immunosuppressant used for the prevention of organ transplant rejection and in the treatment of autoimmune diseases [10] has been linked with several adverse effects including toxicities (nephrotoxicity, hepatoxicity and neurotoxicity), hypertension, dyslipidemia, gingival hyperplasia, hypertrichosis, malignancies and increased risk of cardiovascular events [11], both in transplant and non-transplant settings (autoimmune disorders). Reactive oxygen species (ROS) production and oxidative stress signaling has been implicated in a variety of renal diseases such as IgA nephropathy and chronic kidney disease [10].…”

“…Reactive oxygen species (ROS) production and oxidative stress signaling has been implicated in a variety of renal diseases such as IgA nephropathy and chronic kidney disease [10]. Indiscriminate usage of C. afer in treatment of diseases in Nigeria and many other countries justify carrying this research and many of its kind.…”

Identification of microRNAs and their target genes in Alport syndrome using deep sequencing of iPSCs samples

“…The activation of the MAPK pathway has been shown to be a potential mechanism involved in kidney disease. Kidney disease can be ameliorated if the MAPK signal pathway is inhibited (Pengal et al, 2011;O'Connell et al, 2012). Our results demonstrated that the MAPK pathway is abnormal in AS patients, which provides an experimental basis for further studies into AS pathogenesis.…”