Angiotensin II-induced signaling pathways in diabetes.
Excessive cellular proliferation is a major contributor to the pathological changes associated with the secondary complications of diabetes. In particular, hyperglycemia (HG)-induced growth of vascular smooth muscle cells (VSMC) and glomerular mesangial cells (GMC) are characteristic features of the cardiovascular and renal complications of diabetes. VSMC and GMC respond to traditional growth factors, however in diabetes this occurs in the context of an environment, enriched in circulating vasoactive mediators and HG. For example, signaling via the angiotensin II (Ang II) pathway has been implicated in the pathogenesis of diabetic vascular disease. Recent findings indicate that HG and Ang II activate intracellular processes, including the polyol pathway and the generation of reactive oxygen species. These pathways activate the JAK (janus kinase)/STAT (signal transducers and activators of transcription) signaling cascades in both VSMC and GMC. Activation of the latter signaling cascade can stimulate excessive proliferation and growth of these cells, contributing to the accelerated atherosclerosis and nephropathy seen in the diabetic state. This review focuses on key factors in the diabetic microenvironment, in particular the interplay between HG, accumulation of advanced glycation end products and Ang II mediated signaling events both in vitro and in vivo.
Marrero
Mario B
MB
Medical College of Georgia, 1459 Laney Walker Boulevard, Augusta, Georgia 30912, USA. mmarrero@mail.mcg.edu
Fulton
David
D
Stepp
David
D
Stern
David M
DM
D000804:Angiotensin II / Q000502:physiology*; D002455:Cell Division; D003920:Diabetes Mellitus / Q000473:pathology / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000473:pathology / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000473:pathology / Q000503:physiopathology*; D005920:Glomerular Mesangium / Q000473:pathology / Q000503:physiopathology; D017127:Glycation End Products, Advanced / Q000502:physiology; D006801:Humans; D006943:Hyperglycemia / Q000473:pathology / Q000503:physiopathology; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D017127:Glycation End Products, Advanced; D017382:Reactive Oxygen Species; D000804:Angiotensin II