Possible Mechanisms of Local Tissue Renin-Angiotensin System Activation in the Cardiorenal Metabolic Syndrome and Type 2 Diabetes Mellitus

Abstract

The role of local tissue renin-angiotensin system (tRAS) activation in the cardiorenal metabolic syndrome (CRS) and type 2 diabetes mellitus (T2DM) is not well understood. To this point, we posit that early redox stress-mediated injury to tissues and organs via accumulation of excessive reactive oxygen species (ROS) and associated wound healing responses might serve as a paradigm to better understand how tRAS is involved. There are at least five common categories responsible for generating ROS that may result in a positive feedback ROS-tRAS axis. These mechanisms include metabolic substrate excess, hormonal excess, hypoxia-ischemia/reperfusion, trauma, and inflammation. Because ROS are toxic to proteins, lipids, and nucleic acids they may be the primary instigator, serving as the injury nidus to initiate the wound healing process. Insulin resistance is central to the development of the CRS and T2DM, and there are now thought to be four major organ systems important in their development. In states of overnutrition and tRAS activation, adipose tissue, skeletal muscle (SkM), islet tissues, and liver (the quadrumvirate) are individually and synergistically related to the development of insulin resistance, CRS, and T2DM. The obesity epidemic is thought to be the driving force behind the CRS and T2DM, which results in the impairment of multiple end-organs, including the cardiovascular system, pancreas, kidney, retina, liver, adipose tissue, SkM, and nervous system. A better understanding of the complex mechanisms leading to local tRAS activation and increases in tissue ROS may lead to new therapies emphasizing global risk reduction of ROS resulting in decreased morbidity and mortality.

Up-Regulation of Renin-Angiotensin System in Diabetes and Hypertension: Implications on the Development of Diabetic Nephropathy

“…The newly discovered components of RAS, such as renin receptor, ACE2, Ang IV and also aliskeren, the renin inhibitor, represent that Description References RAS up regulation  Renal Ang II increase  AT1R activation -organ damage  Increased AGT expression -diabetic nephropathy  Increased mRNA levels of ACE, prorenin and cathepsin B.  Ang I increase and renin/neutral endopeptidase activation Lewis et al, 1993Lewis et al, , 2001Zimpelman et al, 2000Hayden et al., 2011. Hsieh et al, 2003.…”

“…This process may result from over production of precursors to reactive oxygen radicals and or decreased efficiency of inhibitory and scavenger systems. In DM, the additional AT1R activation results in a vicious cycle of ROS production which contributes to organ damage (Hayden et al;. The mechanisms that contribute to increased oxidative stress in diabetes may include not only increased non enzymatic glycosylation (glycation) and autoxidative glycosylation (Baynes, 1991), but it is also related to several abnormalities, including hyperglycemia, insulin resistance, hyperinsulinemia and dyslipidemia, each of which contributes to mitochondrial superoxide overproduction in endothelial cells in large and small vessels as well as the myocardium.…”

“…The system has been strongly implicated in the pathophysiology of diabetic renal disease on the basis of its ability to promote tissue remodeling (proliferation, hypertrophy and differentiation) and extracellular matrix remodeling repair and/or fibrosis (Hayden et al; and of the therapeutic ability of angiotensin I-converting enzyme inhibitors (ACEi) and AT1 receptor blockers (ARB) to decrease microalbuminuria and the progression of DN to ESRD (Brenner et al;Chan et al;; Heart Outcomes Prevention Evaluation [HOPE] Study Investigators; Parving et al;. Furthermore, it has been postulated that in diabetes there is a role for the RAS in mediating many of the functional effects, such as changes in intraglomerular hemodynamics as well as structural changes in the diabetic kidney at both glomerular and tubulointerstitial levels .…”

Perivascular adipose tissue: role in the pathogenesis of obesity, type 2 diabetes mellitus and cardiovascular pathology.

“…Активация тканевой ренин-ангиотензиновой системы в периваскулярной жировой ткани может быть связана с формированием стойкого провоспалительного со-стояния и фиброза, с потерей способности периваску-лярной жировой ткани регулировать работу сосудистой стенки. Данные изменения рассматриваются как еще один механизм, связывающий периваскулярную жиро-вую ткань с развитием ожирения и СД2 [40].…”

Neuropeptides, Trophic Factors, and Other Substances Providing Morphofunctional and Metabolic Protection in Experimental Models of Diabetic Retinopathy

“…The major factor driving the vascularization and neovascularization is VEGF. Reducing VEGF levels is therefore a major target in preventing DR. Anti-VEGF therapies in the treatment of proliferative DR and the use of intravitreal anti-VEGF therapy and anti-VEGF traps in clinical practice are now encouraged as adjuncts to corrective surgery (Hayden et al, 2011). It is safe and efficacious for macular condition in humans, although vitreal administration may be associated with an increased risk of systemic thromboembolism (Zhang et al, 2009a).…”