Functional adrenergic system in renal perivascular adipose tissue (PVAT)

Abstract

Obesity is increasing at an alarming rate throughout the world. Today more than 300 million people are obese. The distribution of body fat is more serious than the excess of total body fat to the development and maintenance of diseases. Distributions of ectopic fat depots, such as in the kidney and vessels, seem to be important contributors to cardiovascular diseases. Individuals with low BMI, but with ectopic fat storage, present high prevalence of diseases associated with risk for those diseases. The perivascular adipose tissue (PVAT) has recently been recognized as a factor in vascular biology, with implications in the pathophysiology of cardiovascular disease. Acting in an endocrine or paracrine manner, PVAT releases a wide range of biologically active molecules. PVAT releases angiotensin peptides, being equipped with an almost complete renin-angiotensin system (RAS). One poorly explored mechanism for the PVAT effects on vascular contraction is sympathetic nervous system (SNS) activity. PVAT can attenuate vessel contraction (aorta and mesenteric arteries of rats) to various agonists including phenylephrine and angiotensin II.PVAT-mediated decrease in contractile responses to norepinephrine in rat aorta pointed to the potential role of PVAT in vascular contraction. PVAT increased the uptake of norepinephrine, explaining the observed reduced contractile response in the presence of PVAT. The anticontractile effect of PVAT in rat aorta is transferrable and adipocyte-derived. Studies conducted by Dr. Stephanie Watts (Michigan State University) pointed out the existence of an active, functional catecholamine pool in rat arterial PVAT. PVAT from aorta and mesenteric arteries in normal rat accumulate significant concentrations of catecholamines, which are able to affect the local vascular function, i.e. there is a dynamic adrenergic system PVAT in contributing to the contraction of the vessels. SNS and RAS, by means of the regulation of the kidneys' activities, are directly involved in regulating cardiovascular functions, such as blood pressure. In addition to physical compression of the kidney due to the adipose tissue accumulation, there is increased number of mechanisms responsible for the abnormal renal function in established obesity, including hyperactivity of the SNS. However, despite the classical recognition of the importance of the kidneys to the control of cardiovascular functions, little is known about the ectopic fat, the PVAT around renal vessels and changes in renal function related to the adrenergic/catecholamines activity. I had the opportunity to develop preliminary experiments in partnership with Dr. Stephanie Watts' (MSU, USA) team and the results show significant amount of catecholamines in kidney PVAT (described in Preliminary Results on the project). However, it is unknown whether these catecholamines are synthesized locally or are captured by PVAT after activation of renal sympathetic nerves. This project will test the global hypothesis whether the renal PVAT (arteries/veins) contains functionally adrenergic system components and if this PVAT are innervated by the SNS. The objectives are to investigate mechanisms related to the synthesis, storage, release and catecholamine metabolism that may be possessed by renal PVAT. This is an open door to hereafter test if this adrenergic environment interferes with the kidney functions control. This study provides support for new knowledge about mechanisms by which PVAT modifies the tone of blood vessels influencing the functions of the kidneys. Since the kidney controls important physiological functions, such as BP, and there is intense interdependence with the SNS, this project implies advances in science of autonomic mechanisms linking renal PVAT and cardiovascular diseases. This approach represents a new focus for therapeutic study of obesity associated with hypertension and other cardiovascular diseases, which are epidemiologically relevant in the world. (AU)