Erk in Kidney Diseases

Acute or chronic kidney injury results from various insults and pathological conditions, and is accompanied by activation of compensatory repair mechanisms. Both insults and repair mechanisms are initiated by circulating factors, whose cellular effects are mediated by activation selective signal transduction pathways. Two main signal transduction pathways are activated during these processes, the phosphatidylinositol 3′ kinase (PI-3K)/mammalian target of rapamycin (mTOR) and the mitogen-activated protein kinase (MAPK) cascades. This review will focus on the latter, and more specifically on the role of extracellular signal-regulated kinase (ERK) cascade in kidney injury and repair

Induction of experimental diabetes and diabetic nephropathy using anomer-equilibrated streptozotocin in male C57Bl/6J mice

Open Access via the Elsevier Agreement This research has been funded by the Medical Research Scotland (PhD-1285-2018), PhD studentship to SEJKS, in partnership with AstraZeneca (Cambridge, United Kingdom).Peer reviewedPublisher PD

Acute hyperglycemia rapidly stimulates VEGF mRNA translation in the kidney. Role of angiotensin type 2 receptor (AT2)

Angiotensin II (Ang II) and vascular endothelial growth factor (VEGF) are important mediators of kidney injury in diabetes. Acute hyperglycemia increased synthesis of intrarenal Ang I and Ang II and resulted in activation of both Ang II receptors, AT1 and AT2, in the kidney. Losartan (specific AT1 antagonist) or PD123319 (specific AT2 antagonist) did not affect hyperglycemia but prevented activation of renal AT1 and AT2, respectively. In murine renal cortex, acute hyperglycemia increased VEGF protein but not mRNA content after 24 h, which suggested translational regulation. Blockade of AT2, but not AT1, prevented increase in VEGF synthesis by inhibiting translation of VEGF mRNA in renal cortex. Acute hyperglycemia increased VEGF expression in wild type but not in AT2 knockout mice. Binding of heterogeneous nuclear ribonucleoprotein K to VEGF mRNA, which stimulates its translation, was prevented by blockade of AT2, but not AT1. The Akt-mTOR-p70(S6K) signaling pathway, involved in the activation of mRNA translation, was activated in hyperglycemic kidneys and was blocked by the AT2 antagonist. Elongation phase is an important step of mRNA translation that is controlled by elongation factor 1A (eEF1A) and 2 (eEF2). Expression of eEF1A and activity of eEF2 was higher in kidney cortex from hyperglycemic mice and only the AT2 antagonist prevented these changes. To assess selectivity of translational control of VEGF expression, we measured expression of fibronectin (FN) and laminin beta 1 (lam beta 1): acute hyperglycemia increased FN expression at both protein and mRNA levels, indicating transcriptional control, and did not affect the expression of lam beta 1. To confirm results obtained with PD123319, we induced hyperglycemia in AT2 knockout mice and found that in the absence of AT2, translational control of VEGF expression by hyperglycemia was abolished. Our data show that acute hyperglycemia stimulates Ang II synthesis in murine kidney cortex, this leads to AT2 activation and stimulation of VEGF mRNA translation, via the Akt-mTOR-p70(S6K) signaling pathway. Our data show that exclusive translational control of protein expression in the kidney by acute hyperglycemia is not a general phenomenon, but do not prove that it is restricted to VEGF. (C) 2010 Elsevier Inc. All rights reserved.American Heart Association[SDG 0630283N]National Institute of Health (NIH)[DK061597]National Institute of Health (NIH)[DK077295]National Institute of Health (NIH)[RC2AGO36613]American Diabetes Association[7-05-RA-60]Veterans Administration Research Servic