Effects of Renin-angiotensin System Blockade on the Renal Dopaminergic System in an Experimental Model of Chronic High-Fat Diet

pp. 423-432

Abstract

Background: The renal dopaminergic system (RDS) exerts natriuretic and diuretic effects through D1 receptors and anti-inflammatory actions through D2 receptors. In contrast, angiotensin II, via AT1 receptors, generates opposite responses. Chronic consumption of high-fat diets (HFD) is associated with increased blood pressure and renal inflammation.

Objective: This study aimed to evaluate the impact of treatment with losartan, an AT1 receptor antagonist, on the RDS, blood pressure, and renal damage induced by a HFD.

Methods: Male Sprague–Dawley rats were studied for 8 weeks and randomly assigned to four experimental groups (n=4–6): control (C), high-fat diet (HFD), control + losartan (CL), and high-fat diet + losartan (HFDL). Systolic blood pressure (SBP), body, and plasmatic and urinary biochemical and metabolic parameters were assessed. Renal function, urinary excretion of L-dopa and dopamine (L-dopa/dopamine index), expression of receptors, dopamine transporters, and markers of inflammation, as well as renal structure and ultrastructure were also evaluated. Statistical analysis was performed using Student's t-test, one-way ANOVA with Tukey's post hoc test, Pearson's correlation, and linear regression. Results are expressed as mean ± standard error and p<0.05 was the level of significance.

Results: Losartan prevented the increase in SBP and the L-dopa/dopamine index (HFD vs. C, p<0.01; HFDL vs. HFD, p<0.01); the reduction in fractional and urinary sodium excretion and diuresis (HFD vs. C, p<0.01; HFDL vs. HFD, p<0.05); and decreased expression of the membrane transporter protein OCTN-1,2,3 (HFD vs. C, p<0.01; HFDL vs. HFD, p<0.05). It avoided overexpression of the dopamine D1 receptor (D1R) and Na+K+ATPase (HFD vs. C, p<0.01; HFDL vs. HFD, D1R p<0.01 and Na+K+ATPase p<0.05) and reduced the activation of nuclear factor kappa B, and transforming growth factor beta 1 (HFDL vs. HFD, p<0.01). It also mitigated structural alterations in the proximal tubules, increased interstitial fibrosis (HFD, p<0.01) and ultrastructural changes in the podocyte pedicels observed in HFD.

Conclusions: Under conditions of chronic consumption of a HFD, early administration of losartan favored RDS activity, prevented an increase in SBP, and attenuated interstitial fibrosis and renal inflammation, contributing to protection against target organ damage.