Renin–Angiotensin System Activation Drives Early Cardiorenal Dysfunction in Normotensive Prediabetes

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Abstract
Introduction: Prediabetes is increasingly recognised as a stage at which cardiovascular and renal dysfunction begin to develop despite the absence of overt metabolic disease. The mechanisms underlying these early alterations remain poorly understood. Because adipose tissues surrounding blood vessels and kidneys can locally generate components of the renin–angiotensin system (RAS), we hypothesised that subclinical RAS activation contributes to early cardiorenal dysfunction in prediabetes. Methods: Using a pre‐established normotensive, non‐obese rat model of prediabetes induced by 12 weeks of mild hypercaloric feeding, we examined the impact of systemic angiotensin II (AngII) elevation and angiotensin‐converting enzyme (ACE) inhibition on cardio‐, cerebro‐ and renovascular function by invasive hemodynamics, ex vivo pressure myography, and ex vivo renal perfusion experiments, respectively. Results: Prediabetic rats exhibited impaired parasympathetic baroreceptor sensitivity and altered renovascular endothelium‐dependent vasodilation despite preserved blood pressure and cardiac function. Systemic AngII infusion further exacerbated autonomic and renovascular dysfunction. In contrast, treatment with a non‐hypotensive dose of the ACE inhibitor captopril restored baroreceptor sensitivity, improved renovascular endothelial function, reduced brainstem inflammation, and attenuated renal tubular fibrosis. Examination of perivascular and perirenal adipose tissues revealed significantly higher protein concentration of ACE1 in prediabetic rats compared to controls. Conclusion: These findings are consistent with an early activation of RAS contributing to subclinical cardiovascular and renal dysfunction during prediabetes independently of hypertension. Targeting RAS signalling at this early stage may therefore represent a strategy to limit progression of cardiorenal complications along the continuum from prediabetes to diabetes.
Funding Information
  • Faculty of Medicine, American University of Beirut (AUB‐MPP #320148)

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