TJ0711, a novel vasodilatory β-blocker, protects SHR rats against hypertension induced renal injury

Abstract

Previous studies suggested that β-blockers with adjunctive α1-blocking activities warrant renoprotective function other than the therapeutic effect on hypertension. The current report is designed to dissect the role of TJ0711, a novel β-blocker with a 1:1 ratio for the β1/α1 blocking activities, in renoprotection in SHR rats. It was noted that TJ0711 possesses similar potency for control of blood pressure as that of Carvedilol. However, TJ0711 is much more potent in terms of protecting SHR rats against hypertension induced renal injury. Specifically, SHR rats treated with 20mg/kg/day of TJ0711 manifested significantly lower levels for urine albumin and total protein. In line with these result, TJ0711 treated rats displayed much less severe pathological changes in the kidneys. Mechanistic studies revealed that TJ0711 improves kidney perfusion during the course of hypertensive insult by enhancing eNOS expression through suppressing inflammatory cytokine secretion. TJ0711 also attenuates Vasohibin-1 expression to prevent HIF-1α from signal-induced degradation, and by which it promotes HO-1 expression to protect SHR rats against oxidative stress induced by hypertension in the kidneys. Together, our data suggest that TJ0711 possesses higher potency for renoprotection while manifesting the similar effect on hypertension therapy as Carvedilol.

Keywords: TJ0711; carvedilol; hypertension; renal injury; renoprotection.

Figure 1

Systolic blood pressure (SBP) in rats before and after drug administration. Each group contains 7 rats. BDA, before drug administration.

Figure 2

Histological analysis of renal sections. A. PAS staining results showing hyaline arteriolosclerosis (indicated by yellow arrows, magnification ×400). B. PAS staining results showing partial glomerular ischemia (magnification ×400). C. HE staining results showing scattered interstitial infiltration of lymphocytes. D. Higher magnification of inset area in Figure 2C (magnification ×400). Infiltrated lymphocytes are indicated by yellow arrows.

Figure 3

ELISA results for serum cytokines. A. Serum levels for TNF-α, IL-1β, and IL-10. B. Serum levels for Adiponection. *, p < 0.05 as compared with that of control rats.

Figure 4

Western blot analysis of eNOS expression levels. A. A representative results for Western blot analysis. B. A bar graphic figure showing the relative eNOS expression levels normalized by GAPDH. Four rats were analyzed for each group. *, p < 0.05 as compared with that of control rats; #, p < 0.05 as compared with that of rats in the Carvedilol group.

Figure 5

Results for HO-1 expression analysis. A. Western blot analysis of HO-1 expression levels. Left: A representative Western blot results. Right: A bar graphic figure showing the average results of all rats analyzed (n = 4). *, p < 0.05 as compared with that of control rats. B. HO-1 immunostaining of renal sections.

Figure 6

Analysis of HIF-1α expression in the kidney. A. Results for Western blot analysis. Relative levels for HIF-1α expression were normalized by β-actin and presented by a bar graphic figure (n = 4). *, p < 0.05 as compared with that of control rats. B. Immunostaining of renal sections for HIF-1α expression.

Figure 7

Expression analysis of Vasohibin-1 in the kidney. A. Western blot analysis of Vasohibin-1 expression in each group, and the bar graphs display the average levels of Vasohibin-1 normalized by GAPDH (n = 4). *, p < 0.05 as compared with that of rats within the control group. B. Immunostaining of Vasohibin-1 in the renal sections.