Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney

Abstract

Essential hypertension is a common disease, yet its pathogenesis is not well understood. Altered control of sodium excretion in the kidney may be a key causative feature, but this has been difficult to test experimentally, and recent studies have challenged this hypothesis. Based on the critical role of the renin-angiotensin system (RAS) and the type I (AT1) angiotensin receptor in essential hypertension, we developed an experimental model to separate AT1 receptor pools in the kidney from those in all other tissues. Although actions of the RAS in a variety of target organs have the potential to promote high blood pressure and end-organ damage, we show here that angiotensin II causes hypertension primarily through effects on AT1 receptors in the kidney. We find that renal AT1 receptors are absolutely required for the development of angiotensin II-dependent hypertension and cardiac hypertrophy. When AT1 receptors are eliminated from the kidney, the residual repertoire of systemic, extrarenal AT1 receptors is not sufficient to induce hypertension or cardiac hypertrophy. Our findings demonstrate the critical role of the kidney in the pathogenesis of hypertension and its cardiovascular complications. Further, they suggest that the major mechanism of action of RAS inhibitors in hypertension is attenuation of angiotensin II effects in the kidney.

Fig. 1.

Blood pressures and urinary sodium excretion in mice after kidney cross-transplantation. (A) Daily, 24-h blood pressures in the experimental groups before (“pre”) and during 21 days of Ang II infusion (∗, P ≤ 0.03 vs. Wild-type; §, P < 0.008 vs. Systemic KO; †, P < 0.006–0.0001 vs. Wild-type). (B) Cumulative sodium excretion during the first 5 days of Ang II infusion. (§, P < 0.02 vs. Kidney KO and P = 0.03 vs. Total KO; ‡, P = 0.03 vs. Kidney KO and Total KO). (C) Change in body weights after 5 days of Ang II infusion. (∗, P = 0.03 vs. “pre”; #, P = 0.05 vs. “pre”).

Fig. 2.

Cardiac hypertrophy with angiotensin II infusion. (A–H) Representative hearts and left ventricular cross-sections after 28 days of Ang II infusion: A and E, Wild-type; B and F, Systemic KO; C and G, Kidney KO; D and H, Total KO. (I) Mean heart-to-body weight ratios after 28 days of Ang II infusion. The dashed line represents the mean heart-to-body weight ratio for noninfused Wild-type mice established in previous experiments in our laboratory (23). Wild-type and Systemic KO groups exhibit significant cardiac hypertrophy. (n ≥ 9 per group; §, P < 0.002 vs. Kidney KO and P = 0.0004 vs. Total KO; ‡, P = 0.003 vs. Kidney KO and P = 0.0008 vs. Total KO). (J) For the entire cohort, there was a significant positive correlation between heart-to-body weight ratio and blood pressure (R = 0.84. P < 0.0001).

Fig. 3.

Cardiac injury after angiotensin II infusion. (A–D) Representative photomicrographs of heart sections stained with Masson trichrome. (Magnification: ×20.) Vascular lesions with perivascular infiltrates, medial expansion, and myocyte injury were common in hearts from the Wild-type (A) and Systemic KO (B) groups, whereas myocardial and vascular morphology were normal in the Kidney KO (C) and Total KO (D) groups. (E) Semiquantitative scoring of cardiac pathology (§, P < 0.002 vs. Kidney KO and P < 0.0003 vs. Total KO; ‡, P < 0.02 vs. Kidney KO and P < 0.004 vs. Total KO).

Fig. 4.

Cardiac gene expression in mice infused with angiotensin II. (A) Expression of ANP and BNP mRNA in hearts (n ≥ 8 per group; §, P = 0.003 vs. Kidney KO and P < 0.002 vs. Total KO; ‡, P = 0.004 vs. Kidney KO and P < 0.003 vs. Total KO; ∗, P = 0.02 vs. Kidney KO and P = 0.002 vs. Total KO; #, P = 0.01 vs. Kidney KO and P < 0.002 vs. Total KO). (B) Ratio of cardiac β-MHC-to-α-MHC mRNA expression in hearts. (§, P = 0.01 vs. Kidney KO and P = 0.03 vs. Total KO; ‡, P = 0.002 vs. Kidney KO and P = 0.01 vs. Total KO).