ANGIOTENSIN II INDUCED HYPERTROPHIC RESPONSES IN DIABETIC NEPHROPATHY: INVOLVEMENT OF HYPOXIA INDUCIBLE FACTOR (HIF)

Abstract

Diabetic nephropathy, a progressive development of renal insufficiency in the setting of hyperglycaemia is the major single cause of chronic renal failure (CRF) in which hypoxia plays a critical role. Over the recent past years, views of Angiotensin II (Ang II) have changed from being a simple vasoconstrictor to that of a complex growth factor mediating effects through diverse signalling pathways. Through increased generation of ROS and activation of redox-sensitive transcription factors, Ang II exerts diverse role in endothelial damage. The mechanisms involved in endothelial dysfunction are not entirely understood. Mechanisms underlying the cellular effects of Ang II seem to occur at the post-receptor level and appear to be associated with hyperactivity of Ang II- stimulated G protein-coupled phospholipases, tyrosine kinase-, and MAP kinase-dependent pathways, as well as with oxidative stress. Interactions between these cascades are highly complex, and dysregulation at any level could manifest as pathological functional sequelae and structural vascular changes. Angiotensin II induces oxidative stress via the activation of NADPH oxidase which damages endothelial cells directly, and results in relative hypoxia due to inefficient cellular respiration. Thus the involvement of hypoxia inducible factor in regulation of these pathophysiological actions seems very promising. There are compelling evidence which show that chronic hypoxia final pathway to ESRD (End stage renal disease), therapeutic approaches which target the chronic hypoxia should prove effective against a broad range of renal diseases and associated vascular dysfunction.