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Background: Early metabolic impairment is associated with significant cardiorenal risk. Specifically, subtle serum insulin and lipids changes in prediabetes trigger cardioautonomic and renovascular deterioration. Interestingly, data from our laboratory suggest that these insidious alterations are triggered by perirenal and perivascular adipose inflammation in response to hypoxia evoked by a localized increase in uncoupling protein1 (UCP1) expression and activity. This affects the adjacent organs in a paracrine manner. Hypothesis: Increased UCP1 expression is triggered by sympathetic stimulation. The sympathovagal imbalance in early metabolic dysfunction underlies the observed localized adipose pool involvement. Pharmacological interventions to offset the sympathetic predominance should prevent increased UCP1 expression and inflammation, and reverse cardiorenal manifestations. Methods: A non-obese prediabetic rat model was induced by twelve weeks of hypercaloric feeding. Moxonidine and galantamine were administered orally at daily doses of 2.4 mg/Kg and 4 mg/Kg for the last two weeks of feeding to reduce and facilitate sympathetic and parasympathetic discharge, respectively. Baroreflex sensitivity and renovascular reactivity were assessed by invasive hemodynamics and in isolated perfused kidneys, respectively. Adipose tissue T Cell distribution and macrophage polarization were examined by flow cytometry. Results: Correcting the autonomic imbalance in prediabetic rats with either moxonidine or galantamine restored cardioautonomic and renovascular activity to those observed in control rats. Although prediabetic rats showed an increased oxidative stress and proinflammatory cytokine production in both adipose pools, no change in T Cell population distribution was observed. However, the increased M 1 /M 2 macrophage polarization profile observed in prediabetic rats was reversed by either drug treatment. This was associated with a normalization of UCP1 expression and hypoxic status. Conclusions: Pharmacological interventions to reverse sympathetic predominance could be of therapeutic value treating perivascular and perirenal adipose inflammation that cause early cardiorenal manifestations of prediabetes.

It has become apparent that major sources of reactive oxygen species (ROS) in mammalian cells are the NADPH oxidases. These multimeric enzymes are composed of membrane-bound catalytic subunits, or Nox enzymes, and a small docking subunit called p22phox. Depending on the Nox isoform, cytosolic regulatory subunits also play a role in their activation. There are 7 Nox isoforms. The first identified was Nox2, also called gp91 phox , which is present in phagocytic cells and is responsible for the oxidative burst. Unlike Nox2, the other Nox enzymes exhibit sustained production of ROS at somewhat lower levels. Their modes of activation differ, as do their cellular distributions. Nox1 through Nox4 are expressed in vascular cells in rodents. Nox5 has been identified in atherosclerotic lesions of humans but is not expressed in rodents. Stimulation of cells with angiotensin II, cytokines, catecholamines, high glucose, or mechanical stretch promotes NADPH oxidase activation, in large part as a result of recruitment of cytosolic subunits to the membrane subunit, leading to the formation of the functional enzyme complex that can transfer electrons to molecular oxygen and the formation of superoxide (O2·−).1 O2·−serves as a progenitor for other ROS, including hydrogen peroxide, peroxynitrite, and hypochlorous acid. Enhanced activity of the NADPH oxidases and increased expression of its subunits occur in many pathological conditions, including hypertension, diabetes mellitus, atherosclerosis, cardiac hypertrophy, and heart failure. Studies of genetically altered mice have shown that the deletion of various NADPH oxidase subunits protects against these diseases and their overexpression promotes pathology.2−4 Article see p 1888 A consequence of excessive ROS formation is loss of endothelial nitric oxide (NO), which can occur by rapid radical-radical reactions with O2·− and other radicals or as a result of dysfunction of the endothelial NO synthase. …