Angiotensin II- and glucose-stimulated extracellular matrix production: mediation by the insulin-like growth factor (IGF) axis in a murine mesangial cell line

Abstract

In diabetic nephropathy, glomerular mesangial cells exhibit aberrant anabolic activity that includes excessive production of extracellular matrix (ECM) proteins, leading to crowding of filtration surface areas and possible renal failure. In the present study, a murine mesangial cell line (MES-13 cells) was studied to determine the roles of the renin-angiotensin system (RAS) and the insulin-like growth factor (IGF) axis in the anabolic response to elevated glucose levels. Culture of MES-13 cells in medium containing supra-physiological glucose concentrations (>5.5 mmol/l) resulted in increased production of ECM proteins including laminin, fibronectin, and heparan sulfate proteoglycan with concurrent increases in IGF-binding protein (IGFBP)-2 production. These responses were blocked by the angiotensin receptor antagonists saralasin and losartan, while exogenous angiotensin II (Ang II) treatment directly stimulated increases in ECM and IGFBP-2. In all experiments, IG-FBP-2 levels were correlated with anabolic activity implicating IGFBP-2 as a possible mediator in cellular responses to high glucose and Ang II. Such mediation appears to involve IGFBP-2 modulation of IGF-I signaling, since all responses to high glucose or Ang II were blocked by immuno-neutralization of IGF-I. These data suggest alterations in the IGF axis as key mechanisms underlying nephropathic responses of mesangial cells to Ang II and high glucose.

Role of guanine-nucleotide exchange factor Epac in renal physiology and pathophysiology

“…ANG II has been implicated in the development of chronic progressive glomerular diseases, and the underlying precise mechanism has been the subject of rigorous investigation for the last two decades. In this regard, suggestions have been made that ANG II induces glomerular injury via perturbations of intrarenal hemodynamics with stimulation of growth factor cytokines and thereby excessive synthesis of ECM by glomerular cells (20). Several factors, such as TGF-␤ and ET-1, have been identified as crucial elements responsible for such an outcome; however, details of signaling pathways leading to such an end result are still somewhat unclear.…”

Hyperglycaemia-induced chemoresistance of prostate cancer cells due to IGFBP2

“…In particular IGFBP2 is considered a key player in PCa progression (Degraff et al 2009), being an established mitogen for PCa cells (Chatterjee et al 2004, Uzoh et al 2011. IGFBP2 is also metabolically controlled (Martin et al 2006) and is up-regulated in response to glucose in murine mesangial cells (Davis et al 2008).…”

Loss of angiotensin-converting enzyme 2 leads to impaired glucose homeostasis in mice

“…One of the most intriguing and clinically relevant findings related to renin-angiotensin system (RAS) inhibitors [1,2] is their ability to delay the onset of type 2 diabetes in high-risk patients with cardiovascular disease. Angiotensin II is both pro-inflammatory [3,4] and pro-oxidant [5,6], resulting in cellular toxicity and apoptosis. The protective effects achieved by blocking RAS in clinical studies remain ambiguous.…”