Differential Effects of Angiotensin II Type-1 Receptor Antisense Oligonucleotides on Renal Function in Spontaneously Hypertensive Rats by Minoru Yoneda,

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Presentation transcript:

Differential Effects of Angiotensin II Type-1 Receptor Antisense Oligonucleotides on Renal Function in Spontaneously Hypertensive Rats by Minoru Yoneda, Hironobu Sanada, Junichi Yatabe, Sanae Midorikawa, Shigeatsu Hashimoto, Midori Sasaki, Tetsuo Katoh, Tsuyoshi Watanabe, Peter M. Andrews, Pedro A. Jose, and Robin A. Felder Hypertension Volume 46(1):58-65 July 1, 2005 Copyright © American Heart Association, Inc. All rights reserved.

Figure 1. Immunoreactive AT1R protein in kidney cortical (left panel) and heart (right panel) membranes. Figure 1. Immunoreactive AT1R protein in kidney cortical (left panel) and heart (right panel) membranes. The densitometric ratio of AT1R and β-actin in scrambled (S) and antisense (A) AT1R ODN-treated rats were compared with vehicle (V)-treated WKY and SHR. The immunoblots of AT1Rs revealed 2 bands between 45 and 48 kDa molecular size markers; the upper band was deemed nonspecific because it persisted with AT1R AS-ODN treatment and was not completely blocked by the immunizing peptide (data not shown). *P<0.05 vs vehicle- and AT1R SC-ODN– treated groups (n=3 per group); ANOVA; Holm–Sidak or Duncan’s test. Minoru Yoneda et al. Hypertension. 2005;46:58-65 Copyright © American Heart Association, Inc. All rights reserved.

Figure 2. Systolic blood pressure in vehicle-, AT1R SC-ODN–, and AS-ODN–treated WKY and SHR. AT1R AS-ODN has only a transient effect on blood pressure in SHR. Blood pressures of SHR are higher than those in WKY in all age groups. &vs vehicle and AT1R SC-ODN SHR; ANOVA; Holm–Sidak or Duncan’s test. Figure 2. Systolic blood pressure in vehicle-, AT1R SC-ODN–, and AS-ODN–treated WKY and SHR. AT1R AS-ODN has only a transient effect on blood pressure in SHR. Blood pressures of SHR are higher than those in WKY in all age groups. &vs vehicle and AT1R SC-ODN SHR; ANOVA; Holm–Sidak or Duncan’s test. Minoru Yoneda et al. Hypertension. 2005;46:58-65 Copyright © American Heart Association, Inc. All rights reserved.

Figure 3. Daily urinary sodium excretion in vehicle-, AT1R SC-ODN–, and AS-ODN–treated WKY and SHR. Three-week-old male WKY and SHR were fed 0.28% NaCl chow and tap water; at 4 weeks of age, the diet was changed to 4% NaCl chow. Figure 3. Daily urinary sodium excretion in vehicle-, AT1R SC-ODN–, and AS-ODN–treated WKY and SHR. Three-week-old male WKY and SHR were fed 0.28% NaCl chow and tap water; at 4 weeks of age, the diet was changed to 4% NaCl chow. P<0.05; &vs vehicle and SC-ODN SHR; *vs others; ANOVA; Holm–Sidak or Duncan’s test. Minoru Yoneda et al. Hypertension. 2005;46:58-65 Copyright © American Heart Association, Inc. All rights reserved.

Figure 4. Daily urinary protein excretion in vehicle-, AT1R SC-ODN–, and AS-ODN–treated WKY and SHR. P<0.05; *vs others, +vs within their respective groups; ANOVA; Holm–Sidak or Duncan’s test. Figure 4. Daily urinary protein excretion in vehicle-, AT1R SC-ODN–, and AS-ODN–treated WKY and SHR. P<0.05; *vs others, +vs within their respective groups; ANOVA; Holm–Sidak or Duncan’s test. Minoru Yoneda et al. Hypertension. 2005;46:58-65 Copyright © American Heart Association, Inc. All rights reserved.

Figure 5. Glomerular histochemistry in vehicle-, AT1R SC-ODN–, and AS-ODN–treated WKY and SHR. At 9 weeks of age, WKY kidneys had normal-appearing glomeruli (a; vehicle-treated WKY) and were not affected by ODN treatment (b, SC-ODN–treated WKY; c, AS-ODN–treated WKY). Figure 5. Glomerular histochemistry in vehicle-, AT1R SC-ODN–, and AS-ODN–treated WKY and SHR. At 9 weeks of age, WKY kidneys had normal-appearing glomeruli (a; vehicle-treated WKY) and were not affected by ODN treatment (b, SC-ODN–treated WKY; c, AS-ODN–treated WKY). However, SHR exhibited glomerulosclerosis as evidenced by an increase in PAS staining (arrows) and associated glomerular degeneration (d; vehicle-treated SHR). Although SC-ODN treatment did not alter SHR glomerular histopathology (e; SC-ODN–treated SHR), there was a dramatic improvement in SHR glomeruli in response to AS-ODN treatment (f; AS-ODN–treated SHR). Bar=100 μm. Minoru Yoneda et al. Hypertension. 2005;46:58-65 Copyright © American Heart Association, Inc. All rights reserved.

Figure 6. GSI evaluated from sections of the different treatment groups in Figure 5. Figure 6. GSI evaluated from sections of the different treatment groups in Figure 5. GSI was scored in 100 glomeruli examined 3× in 3 different slides. S indicates scrambled; A, antisense; V, vehicle. *P<0.05 vs other groups. Minoru Yoneda et al. Hypertension. 2005;46:58-65 Copyright © American Heart Association, Inc. All rights reserved.