Now showing 1 - 6 of 6
  • Publication
    The Role of MAPK in Drug-Induced Kidney Injury
    This paper focuses on the role that mitogen-activated protein kinases (MAPKs) play in drug-induced kidney injury. The MAPKs, of which there are four major classes (ERK, p38, JNK, and ERK5/BMK), are signalling cascades which have been found to be broadly conserved across a wide variety of organisms. MAPKs allow effective transmission of information from the cell surface to the cytosolic or nuclear compartments. Cross talk between the MAPKs themselves and with other signalling pathways allows the cell to modulate responses to a wide variety of external stimuli. The MAPKs have been shown to play key roles in both mediating and ameliorating cellular responses to stress including xenobiotic-induced toxicity. Therefore, this paper will discuss the specific role of the MAPKs in the kidney in response to injury by a variety of xenobiotics and the potential for therapeutic intervention at the level of MAPK signalling across different types of kidney disease.
      717
  • Publication
    Sirolimus enhances cyclosporine a-induced cytotoxicity in human renal glomerular mesangial cells
    End Stage Renal Disease (ESRD) is an ever increasing problem worldwide. However the mechanisms underlying disease progression are not fully elucidated. This work addressed the nephrotoxicity induced by the immunosuppressive agents’ cyclosporine A (CsA) and sirolimus (SRL). Nephrotoxicity is the major limiting factor in the long term use of CsA. SRL causes less nephrotoxicity than CsA. Therefore investigations into the differential effects of these agents may identify potential mechanisms of nephrotoxicity and possible means to prevent ESRD induced by therapeutic drugs. Using ELISA, western blotting, quantitative PCR and a reporter gene assay we detailed the differential effects of the immunosuppressive agents CsA, and SRL in human renal mesangial cells. CsA treatment increased profibrotic TGF-β1 secretion in human mesangial cells whereas SRL did not, indicating a role for TGF-β in CsA toxicity. However we observed a synergistic nephrotoxic effect when CsA and SRL were co-administered. These synergistic alterations may have been due to an increase in CTGF which was not evident when the immunosuppressive drugs were used alone. The CsA/SRL combination therapy significantly enhanced Smad signalling and altered the extracellular matrix regulator matrix metalloproteinase 9 (MMP-9). Inhibition of the ERK 1/2 pathway, attenuated these CsA/SRL induced alterations indicating a potentially significant role for this pathway.
      339
  • Publication
    Mechanisms of calcineurin inhibitor nephrotoxicity in chronic allograft injury
    The first successful transplantation of a human kidney was performed more than 50 years ago by Murray and colleagues in 1954 between identical twins. The success of this transplantation was due to the fact that no significant rejection occurs between genetically identical twins and therefore immunosuppression was not necessary in this particular case (Merrill et al., 1956). However, solid-organ transplantation could not be considered truly successful until the 1970’s after significant technical and pharmacological advances. In particular, the discovery and development of the calcineurin inhibitors (CNIs) has made allograft transplantation routinely successful with greatly reduced risk of acute rejection. In the absence of pharmacological agents to address the primary pathological mechanisms involved, renal transplantation has now been the standard management of end stage renal failure for the past four decades (Wolfe et al., 1999). Short-term renal allograft and allograft recipient survival rates have increased significantly during the last decade largely due to improved patient monitoring. However, allograft half-life beyond 1 year post-transplant remains largely unchanged. While rates of early allograft failure have significantly reduced, late renal allograft dysfunction remains a significant problem in the transplant population (de Fijter). Chronic allograft injury (CAI) is the most prevalent cause of allograft dysfunction in the first decade after transplantation. The term CAI is used to describe deterioration of renal allograft function and structure due to immunological processes (i.e. chronic rejection) and/or a range of simultaneous nonimmunological factors such as CNI-induced nephrotoxicity, hypertension and infection. This chapter will outline the pathophysiology and etiology of CAI and the role that CNI nephrotoxicity plays in this disease process. It will also review experimental studies that have identified important molecular mechanisms involved and discuss strategies utilised to minimise the development and progression of CAI.
      1226
  • Publication
    Identification of novel indicators of cyclosporine A nephrotoxicity in a CD-1 mouse model
    The calcineurin inhibitor cyclosporine A (CsA) is a widely used immunosuppressive agent. However,nephrotoxicity is a serious side effect observed in patients which limits clinical use of CsA. CsA nephrotoxicity is associated with tubulointerstitial injury progressing to nephropathy. This is typically diagnosed by invasive renal biopsy and is often only detected when the disease process is well advanced. Therefore identification of novel, early indicators of CsA nephrotoxicity could be clinically advantageous. This study aimed to establish a murine model of CsA nephrotoxicity and to identify urinary proteins that may indicate the onset of CsAinduced nephropathy using 2-D gel electrophoresis. CsA nephrotoxicity was induced in CD-1 mice by daily CsA administration for 4 weeks. By week 4, elevated serum creatinine and proteinuria were observed after CsA treatment indicating significant renal dysfunction. Decreased cadherin-1, increased α-smooth muscle actin and fibroblast specific protein 1 in kidney tissue indicated disruption of normal tubular architecture. Alterations in podocin and uromodulin were also observed which may indicate damage to other segments of the nephron. Proteomic analysis of urine identified a number of differentially regulated proteins that may be involved in early CsA nephropathy including cadherin 1, superoxide dismutase and vinculin. These findings suggest novel mechanisms of CsA nephrotoxicity and identify novel potential markers of the disease.
      1040Scopus© Citations 15
  • Publication
    Identification of β2-microglobulin as a urinary biomarker for chronic allograft nephropathy using proteomic methods
    Chronic allograft nephropathy (CAN) remains the leading cause of renal graft loss after the first year following renal transplantation. This study aimed to identify novel urinary proteomic profiles, which could distinguish and predict CAN in susceptible individuals. Experimental Design: The study included 34 renal transplant patients with histologically proven CAN and 36 patients with normal renal transplant function. High-throughput proteomic profiles were generated from urine samples with three different ProteinChip arrays by surface-enhanced laser-desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). Following SELDI a biomarker pattern software analysis was performed which led to the identification of a novel biomarker pattern that could distinguish patients with CAN from those with normal renal function. Results: An 11.7 kDa protein identified as β2 microglobulin was the primary protein of this biomarker pattern, distinguishing CAN from control patients (ROC = 0.996). SELDI-TOF-MS comparison of purified β2 microglobulin protein and CAN urine demonstrated identical 11.7 kDa protein peaks. Significantly higher concentrations of β2 microglobulin were found in the urine of patients with CAN compared to the urine of normal renal function transplant recipients (p<0.001). Conclusions and clinical relevance: Whilst further validation in a larger more diverse patient population is required to determine if this β2 microglobulin protein biomarker will provide a potential means of diagnosing CAN by non-invasive methods in a clinical setting, this study clearly shows a capability to stratify control and disease patients.
      957Scopus© Citations 20
  • Publication
    High-mobility group box protein 1: a novel mediator of inflammatory-induced renal epithelial-mesenchymal transition
    Background: High mobility group box protein 1 (HMGB-1) is a chromatin binding protein that bends DNA thereby facilitating gene transcription. HMGB-1 has also been observed as an extracellular secreted protein in serum of patients with sepsis and has putative intracellular signalling effects regulating the production of interleukin-1 and tumour necrosis factor in a number of inflammatory conditions. Methods: We established a model of immune-mediated epithelial-mesenchymal transition (EMT) in human proximal tubular epithelial cells (PTECs). PTECs were cultured with conditioned medium containing supernatant from activated peripheral blood mononuclear cells (aPBMC). The model was characterised using phenotypic and transcriptomic approaches and suppression subtractive hybridisation was performed to identify differentially regulated genes. Results. Activation of PBMCs resulted in increased secretion of HMGB-1. In addition, treatment of PTECs with aPBMC-conditioned medium resulted in significant upregulation of HMGB-1 in PTECs. Direct treatment of PTECs with recombinant human HMGB-1 induced alterations in epithelial morphology consistent with EMT including reduced E-cadherin expression, increased α-SMA expression and enhanced cell migration. HMGB-1 effects were mediated at least in part by the receptor for advanced glycation end products (RAGE) and through induction of TGF-β1 secretion from PTECs. Conclusions. These results suggest that HMGB-1 is a key mediator of immune-mediated EMT of PTECs and a potentially important signalling molecule in the development of renal fibrosis.
      488Scopus© Citations 47