Liver steatosis, cardiac and renal fibrosis, and hypertension in overweight rats: Angiotensin-(3-4)-sensitive hepatocardiorenal syndrome

Abstract

Overweight/obesity is a growing pandemic that affects many organs and tissues. We have investigated whether a high-lipid diet provokes an imbalance between type 1 and type 2 angiotensin II (Ang II) receptors signaling, leading to liver alterations associated with cardiovascular and kidney disturbances. Chronic administration of a high-lipid diet can provoke hepatocardiorenal syndrome resulting from activation of the Ang II→type 1 receptor axis, which is entirely counteracted by Ang-(3-4), the allosteric enhancer of the Ang II→type 2 receptor pathway.

Keywords: Arterial hypertension; Cardiac and renal fibrosis; Hepatocardiorenal syndrome; Hyperlipidic diet; Non-alcoholic liver steatosis; Overweight rats.

Graphical abstract

Fig. 1

Picrosirius staining of the left ventricle and renal cortex, and systolic blood pressure in rats given control (CTR) and high-lipid content (HL) diets. (A, B) Representative images from left ventricular tissue. (C, D) Representative images from renal cortical tissue. (E, F) Graphical representation of the surface areas of the collagen network as stained by picrosirius red in cardiac and renal tissues, respectively. Left ventricle CTR: n = 4 rats; total analysed areas = 40. Left ventricle HL: n = 5 rats; total analysed areas = 50. Renal cortex CTR: n = 4 rats; total analysed areas = 40. Renal cortex HL: n = 5 rats; total analysed areas = 50. Differences were assessed using unpaired Student's t-test. P values are indicated within the panels. (G) Systolic blood pressure of CTR and HL rats aged 164 days that received or not Ang-(3–4) between days 162 and 164 of age. (H) Diastolic blood pressure of the same rats. Values are mean ± SEM. Differences were assessed using one-way ANOVA followed by Bonferroni's test for selected pairs. P values are indicated within the panel. CTR: n = 17; HL: n = 12; CTR + Ang-(3–4): n = 13; HL + Ang-(3–4): n = 14. The animals were the same immediately used for ultrasound studies (see Fig. 2). In one rat from this ensemble, liver position relative to kidney did not allow recording of adequate images. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Hepatorenal index (mean hepatic brightness/mean renal brightness) in rats given control (CTR) and high-lipid content (HL) diets: effect of Ang-(3–4). (A, B, C, D) Representative abdominal ultrasound images from CTR, HL, CTR + Ang-(3–4), and HL + Ang-(3–4) rats, respectively. Ang-(3–4) was administered as described in the text. The organs are identified by their initial letters L (liver) and K (kidney), and the images were processed as described in the text. (E) Graphic representation of the pixels densities in CTR (n = 17), HL (n = 12), CTR + Ang-(3–4) (n = 12), and HL + Ang-(3–4) (n = 14) rats. Values are mean ± SEM. Using one-way ANOVA followed by Bonferroni's test for selected pairs assessed differences. P values are indicated within the panel.