Amelioration of Cardiac Autonomic Dysfunction Mitigates Perivascular and Perirenal Adipose Inflammation and Cardiorenal Involvement in Prediabetes.

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 M1 /M2 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.