Renin-Angiotensin-System imbalance contributes to cardiac autonomic and renal dysfunction in early metabolic challenge.

Abstract

Cardiac and Reno vascular complications remain the major cause of morbidity and mortality associated with type 2 diabetes mellitus (T2DM). A growing body of evidence suggest that these complications can commence as early as the pre-diabetic stage before the appearance of frank hyperglycemia, this implicated the presence of mechanisms apart from those related to serum glucose control as a root cause of such pathology. Literature describes that poor cardiovascular (CV) outcomes linked to obesity can result from the interaction between adipose tissue (AT) and the Renin-Angiotensin-Aldosterone System (RAAS). Indeed, Angiotensin II (Ang II) the main effector of RAAS is known to be a resultant of and a contributor to AT inflammation and CV anomalies. Emerging data revealed that perivascular (PVAT) and perirenal (PRAT) adipose tissue inflammation play a role in the development of cardiac autonomic neuropathy (CAN) and kidney diseases respectively during early stages of metabolic derangement i.e. pre-diabetes (PD), however, whether there is increased production or sensitivity to Ang II at the levels of both PVAT and PRAT during the pre-diabetic stage has not been forthcoming. To investigate for that, the mildly increased caloric intake (HC)-fed rat model developed in our laboratory was used. This model shows all salient features of PD in the absence of hyperglycemia and hypertension. Control and HC Sprague-Dawley rats were fed their corresponding diets for 12 weeks, a solution containing either a slow-pressor dose of Ang II (0.8mg/kg/day) or a vehicle was subcutaneously infused during the last 2 weeks of feeding and two additional groups (fed either diet) received a three-week treatment of a non-hypotensive dose (10mg/kg) of an Angiotensin converting enzyme inhibitor, captopril. Both Ang II –treated groups and HC-fed rats showed a deterioration in the cardiac autonomic control affecting the parasympathetic activity as compared to their control counter parts .This parasympathetic CAN was further worsened in the HC-Ang II treated rats and treatment with captopril significantly improved the CAN phenotype in the HC group which might be indicative of an endogenous Ang II component contributing to the phenotype. Isolated perfused kidneys of HC-fed rats showed a normal reno-vascular relaxation that was not mediated by nitric oxide and prostaglandins as in controls, however the usage of captopril attenuated the response and preserved the vasodilatory endothelial mediators in these PD rats, on the other side, those effects were much more exacerbated in the perfused kidneys of HC-Ang II rats which showed a complete loss of all vasodilatory endothelial mediators and that explained the hypertensive phenotype observed in this group as well it further highlights the possibility of HC-diet associated increase in production of or sensitivity to Ang II .The present results suggest that local PVAT and PRAT RAAS might be activated during early metabolic derangement and a sub-depressor dose of captopril might have a protective effect against these metabolic-induced pathologies.