Abstract
Extracellular-signal regulated kinase (ERK) activation by MEK plays a key role in many of the cellular processes that underlie progressive kidney fibrosis including cell proliferation, apoptosis and transforming growth factor β1-mediated epithelial to mesenchymal transition. We therefore assessed the therapeutic impact of ERK1/2 inhibition using a MEK inhibitor in the rat 5/6 subtotal nephrectomy (SNx) model of kidney fibrosis. There was a twentyfold upregulation in phospho-ERK1/2 expression in the kidney after SNx in Male Wistar rats. Rats undergoing SNx became hypertensive, proteinuric and developed progressive kidney failure with reduced creatinine clearance. Treatment with the MEK inhibitor, CI-1040 abolished phospho- ERK1/2 expression in kidney tissue and prevented phospho-ERK1/2 expression in peripheral lymphocytes during the entire course of therapy. CI-1040 had no impact on creatinine clearance, proteinuria, glomerular and tubular fibrosis, and α-smooth muscle actin expression. However, inhibition of ERK1/2 activation led to significant compensatory upregulation of the MAP kinases, p38 and JNK in kidney tissue. CI-1040 also increased the expression of plasminogen activator inhibitor-1 (PAI-1), a key inhibitor of plasmin-dependent matrix metalloproteinases. Thus inhibition of ERK1/2 activation has no therapeutic effect on kidney fibrosis in SNx possibly due to increased compensatory activation of the p38 and JNK signalling pathways with subsequent upregulation of PAI-1.
Highlights
Irrespective of the underlying insult, progressive chronic kidney disease (CKD) is characterised by glomerulosclerosis, tubulointerstitial fibrosis, tubular atrophy and capillary loss
We examined the effects of inhibiting extracellular signal-regulated kinase1/2 (ERK1/2) activation with CI-1040 in the 5/6 subtotal nephrectomy (SNx) model, which is a well-characterised model of progressive kidney fibrosis and excretory kidney failure [23]
The key finding of this study is that MEK inhibition with CI-1040 after SNx results in compensatory upregulation of other mitogen-activated protein kinases (MAPKs) such as p38, Jun N-terminal kinase (JNK) as well as increased expression of plasminogen activator inhibitor-1 (PAI-1), which is well characterised as having both pro-fibrotic and anti-fibrinolytic properties [24]
Summary
Irrespective of the underlying insult, progressive chronic kidney disease (CKD) is characterised by glomerulosclerosis, tubulointerstitial fibrosis, tubular atrophy and capillary loss. ERK Inhibition and Kidney Fibrosis inflammatory cells, release of fibrogenic growth factors, tubular epithelial to mesenchymal transition (EMT), activation and proliferation of fibroblasts with subsequent accumulation of extracellular matrix (ECM) [1, 2]. The mitogen-activated protein kinases (MAPKs) are a family of serine/threonine kinases that regulate many cellular processes central to kidney fibrogenesis including cell proliferation, apoptosis, EMT and ECM deposition [6]. The three best characterised members of the family, extracellular signal-regulated kinase1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38MAPK all appear to be activated in response to renal injury and contribute to the fibrotic response [6]. ERK1/2 is activated by the Ras-Raf-Mek-ERK signalling pathway as a result of cell-surface receptor activation by mitogenic growth factors. A variety of scaffold proteins including KSR1/2, IQGAP1, MP1, β-Arrestin1/2 have been shown to regulate Erk1/2 activity [10]
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