Yoshie Arai

Renal Sympathetic Denervation Suppresses De Novo Podocyte Injury and Albuminuria in Rats With Aortic Regurgitation

Background— The presence of chronic kidney disease is a significant independent risk factor for poor prognosis in patients with chronic heart failure. However, the mechanisms and mediators underlying this interaction are poorly understood. In this study, we tested our hypothesis that chronic cardiac volume overload leads to de novo renal dysfunction by coactivating the sympathetic nervous system and renin-angiotensin system in the kidney. We also examined the therapeutic potential of renal denervation and renin-angiotensin system inhibition to suppress renal injury in chronic heart failure. Methods and Results— Sprague-Dawley rats underwent aortic regurgitation and were treated for 6 months with vehicle, olmesartan (an angiotensin II receptor blocker), or hydralazine. At 6 months, albuminuria and glomerular podocyte injury were significantly increased in aortic regurgitation rats. These changes were associated with increased urinary angiotensinogen excretion, kidney angiotensin II and norepinephrine (NE) levels, and enhanced angiotensinogen and angiotensin type 1a receptor gene expression and oxidative stress in renal cortical tissues. Aortic regurgitation rats with renal denervation had decreased albuminuria and glomerular podocyte injury, which were associated with reduced kidney NE, angiotensinogen, angiotensin II, and oxidative stress. Renal denervation combined with olmesartan prevented podocyte injury and albuminuria induced by aortic regurgitation. Conclusions— In this chronic cardiac volume-overload animal model, activation of the sympathetic nervous system augments kidney renin-angiotensin system and oxidative stress, which act as crucial cardiorenal mediators. Renal denervation and olmesartan prevent the onset and progression of renal injury, providing new insight into the treatment of cardiorenal syndrome.

Soluble (pro)renin receptor and blood pressure during pregnancy : a prospective cohort study

The renin–angiotensin system is believed to influence blood pressure (BP) during pregnancy, but the associations between BP during pregnancy and the soluble form of the (pro)renin receptor (s[P]RR), a new component of the tissue renin–angiotensin system, remain undetermined. In this prospective cohort study of 437 pregnant women with normal BP (systolic <140 mm Hg and diastolic <90 mm Hg) during early pregnancy (<16 weeks of gestation) regression analysis was performed to examine the associations between plasma s(P)RR concentrations and BP in 3 gestational stages (20–24, 28–32, and 36–40 weeks of gestation) and logistic regression analysis to evaluate the incidence of preeclampsia. Plasma s(P)RR concentrations at early, middle (16–28 weeks), and late pregnancy (>28 weeks) and at delivery averaged 29.7 ± 10.0, 31.3 ± 12.0, 39.2 ± 8.9, and 40.4 ± 10.2 ng/mL (mean±SD), respectively. A 1-ng/mL increase in plasma s(P)RR concentration in early pregnancy predicted systolic/diastolic BP elevation in the later 3 gestational stages: 0.11 (95% CI, 0.014–0.20)/0.093 (0.027–0.16) mm Hg for 20 to 24 weeks, 0.11 (0.029–0.19)/0.088 (0.027–0.15) mm Hg for 28 to 32 weeks, and 0.16 (0.058–0.26)/0.12 (0.043–0.19]) mm Hg for 36 to 40 weeks, respectively. Plasma s(P)RR concentrations in middle and late pregnancy were not associated with BP. Adjusted models revealed that women with plasma s(P)RR concentrations above the 75th percentile at delivery had a significantly increased risk of preeclampsia (odds ratio, 22.5 [95% CI, 1.8–279.9]). In conclusion, high circulating levels of s(P)RR at early pregnancy predicted a subsequent elevation in BP, and high concentrations at delivery were significantly associated with preeclampsia.

Aliskiren binds to renin and prorenin bound to (pro)renin receptor in vitro

Human (pro)renin receptor ((P)RR) has been implicated in the augmentation of many biological and cellular processes through bindings to its ligands, renin and prorenin. In this study, we investigated the effects of aliskiren, a direct oral renin inhibitor, on the activities of free and (P)RR-bound forms of human mature renin. We also elucidated the effect of aliskiren on the ‘renin activity’ of the receptor-bound form of prorenin. Aliskiren had an IC50 of 0.72 nmol l−1 against renin. The compound competitively inhibited renin activity with an inhibitory constant (Ki) of 0.18 nmol l−1. Furthermore, the dissociation constants (KD) for aliskiren from renin and prorenin bound to (P)RR were determined using surface plasmon resonance in a BIAcore assay system (Uppsala, Sweden). These values were estimated to be 0.46±0.03 and 0.25±0.01 nmol l−1, respectively. The compound competitively inhibited the renin activities of (P)RR-bound forms of both renin and prorenin with a Ki of 0.14 and 0.15 nmol l−1, respectively. These results indicate that aliskiren could be a potent inhibitor of the free forms of mature renin and of the receptor-bound forms of renin and prorenin.

Qualitative and quantitative analyses of (pro)renin receptor in the medium of cultured human umbilical vein endothelial cells

A 30-kDa protein in the medium of cultured human umbilical vein endothelial cells (HUVECs) was identified as (pro)renin receptor, (P)RR, by western blot analysis using anti-human (P)RR antibodies. The protein bound recombinant human prorenin with a KD of 4.0 nmol l−1 and activated prorenin. These observations suggest the presence of soluble (P)RR, s(P)RR, in the medium of cultured HUVECs. For quantification of the s(P)RR in the medium, an enzyme-linked immunosorbent assay (ELISA) was established. The quantitative range of the ELISA was validated over a nominal range of 7.5–300 pmol l−1 in the wells of a microtiter plate. The assay system showed good linearity (r2=0.99) with interassay (5.8–9.7%) and intraassay (2.1–7.0%) precision. Using this method, the concentration of s(P)RR in the culture medium of HUVECs was measured to be 32 pmol l−1. Therefore, these results show qualitative and quantitative evidence that prorenin can be activated after binding to s(P)RR secreted from cultured HUVECs.

Soluble (Pro)Renin Receptor and Blood Pressure During Pregnancy

The renin–angiotensin system is believed to influence blood pressure (BP) during pregnancy, but the associations between BP during pregnancy and the soluble form of the (pro)renin receptor (s[P]RR), a new component of the tissue renin–angiotensin system, remain undetermined. In this prospective cohort study of 437 pregnant women with normal BP (systolic <140 mm Hg and diastolic <90 mm Hg) during early pregnancy (<16 weeks of gestation) regression analysis was performed to examine the associations between plasma s(P)RR concentrations and BP in 3 gestational stages (20–24, 28–32, and 36–40 weeks of gestation) and logistic regression analysis to evaluate the incidence of preeclampsia. Plasma s(P)RR concentrations at early, middle (16–28 weeks), and late pregnancy (>28 weeks) and at delivery averaged 29.7 ± 10.0, 31.3 ± 12.0, 39.2 ± 8.9, and 40.4 ± 10.2 ng/mL (mean±SD), respectively. A 1-ng/mL increase in plasma s(P)RR concentration in early pregnancy predicted systolic/diastolic BP elevation in the later 3 gestational stages: 0.11 (95% CI, 0.014–0.20)/0.093 (0.027–0.16) mm Hg for 20 to 24 weeks, 0.11 (0.029–0.19)/0.088 (0.027–0.15) mm Hg for 28 to 32 weeks, and 0.16 (0.058–0.26)/0.12 (0.043–0.19]) mm Hg for 36 to 40 weeks, respectively. Plasma s(P)RR concentrations in middle and late pregnancy were not associated with BP. Adjusted models revealed that women with plasma s(P)RR concentrations above the 75th percentile at delivery had a significantly increased risk of preeclampsia (odds ratio, 22.5 [95% CI, 1.8–279.9]). In conclusion, high circulating levels of s(P)RR at early pregnancy predicted a subsequent elevation in BP, and high concentrations at delivery were significantly associated with preeclampsia.

Acid-activated prorenin binds to (pro)renin receptor in vitro

Binding properties of acid-activated prorenin to (pro)renin receptor [(P)RR] was investigated in vitro to discuss possible roles of such reversibly acid-activated prorenin in the renin angiotensin (RA) system. Prorenin was acidified at pH 3.3, 4.5, 5.5, 6.5, and its activation level was measured at 1, 2, 4, 8, 12, and 25 h. Prorenin, activated non-proteolytically in time- and pH-dependent manners, was verified by Western blot analyses. Acidification of prorenin for 25 h at pH 3.3, 4.5, 5.5, and 6.5 showed 78%, 54%, 34%, and 20% activities, respectively when compared with the renin activity of trypsinized prorenin as 100%. Additionally, the binding properties of acidified prorenin to (P)RR were elucidated both at the equilibrium state and in the kinetic state using BIAcore. BIAcore assay showed that acidified prorenin at pH 3.3, 4.5, 5.5, and 6.5 had apparent K(D) of 1.57 × 10(4), 14.1, 8.29, and 8.04 nM, respectively while native prorenin at pH 7.4 had a K(D) of 7.8 nM. At equilibrium state, K(D) of native prorenin was 1.42 nM whereas apparent K(D) varied from 1.25 to 5.0 nM for the prorenin acidified at pH 4.5, 5.5, and 6.5. The K(m) values of free forms of acidified prorenin at different pH (0.33-0.5 μM) was almost similar to those of (P)RR-bound forms of acidified prorenin (0.5-0.77 μM). These in vitro data indicate that prorenin acidified in vivo possibly modulate RA system in receptor-dependent and/or -independent manners which could ultimately lead to the pathogenesis of diseases.

Soluble (Pro)Renin Receptor and Blood Pressure During PregnancyNovelty and Significance

The renin–angiotensin system is believed to influence blood pressure (BP) during pregnancy, but the associations between BP during pregnancy and the soluble form of the (pro)renin receptor (s[P]RR), a new component of the tissue renin–angiotensin system, remain undetermined. In this prospective cohort study of 437 pregnant women with normal BP (systolic <140 mm Hg and diastolic <90 mm Hg) during early pregnancy (<16 weeks of gestation) regression analysis was performed to examine the associations between plasma s(P)RR concentrations and BP in 3 gestational stages (20–24, 28–32, and 36–40 weeks of gestation) and logistic regression analysis to evaluate the incidence of preeclampsia. Plasma s(P)RR concentrations at early, middle (16–28 weeks), and late pregnancy (>28 weeks) and at delivery averaged 29.7 ± 10.0, 31.3 ± 12.0, 39.2 ± 8.9, and 40.4 ± 10.2 ng/mL (mean±SD), respectively. A 1-ng/mL increase in plasma s(P)RR concentration in early pregnancy predicted systolic/diastolic BP elevation in the later 3 gestational stages: 0.11 (95% CI, 0.014–0.20)/0.093 (0.027–0.16) mm Hg for 20 to 24 weeks, 0.11 (0.029–0.19)/0.088 (0.027–0.15) mm Hg for 28 to 32 weeks, and 0.16 (0.058–0.26)/0.12 (0.043–0.19]) mm Hg for 36 to 40 weeks, respectively. Plasma s(P)RR concentrations in middle and late pregnancy were not associated with BP. Adjusted models revealed that women with plasma s(P)RR concentrations above the 75th percentile at delivery had a significantly increased risk of preeclampsia (odds ratio, 22.5 [95% CI, 1.8–279.9]). In conclusion, high circulating levels of s(P)RR at early pregnancy predicted a subsequent elevation in BP, and high concentrations at delivery were significantly associated with preeclampsia.

Soluble (Pro)Renin Receptor and Blood Pressure During PregnancyNovelty and Significance: A Prospective Cohort Study

The renin–angiotensin system is believed to influence blood pressure (BP) during pregnancy, but the associations between BP during pregnancy and the soluble form of the (pro)renin receptor (s[P]RR), a new component of the tissue renin–angiotensin system, remain undetermined. In this prospective cohort study of 437 pregnant women with normal BP (systolic <140 mm Hg and diastolic <90 mm Hg) during early pregnancy (<16 weeks of gestation) regression analysis was performed to examine the associations between plasma s(P)RR concentrations and BP in 3 gestational stages (20–24, 28–32, and 36–40 weeks of gestation) and logistic regression analysis to evaluate the incidence of preeclampsia. Plasma s(P)RR concentrations at early, middle (16–28 weeks), and late pregnancy (>28 weeks) and at delivery averaged 29.7 ± 10.0, 31.3 ± 12.0, 39.2 ± 8.9, and 40.4 ± 10.2 ng/mL (mean±SD), respectively. A 1-ng/mL increase in plasma s(P)RR concentration in early pregnancy predicted systolic/diastolic BP elevation in the later 3 gestational stages: 0.11 (95% CI, 0.014–0.20)/0.093 (0.027–0.16) mm Hg for 20 to 24 weeks, 0.11 (0.029–0.19)/0.088 (0.027–0.15) mm Hg for 28 to 32 weeks, and 0.16 (0.058–0.26)/0.12 (0.043–0.19]) mm Hg for 36 to 40 weeks, respectively. Plasma s(P)RR concentrations in middle and late pregnancy were not associated with BP. Adjusted models revealed that women with plasma s(P)RR concentrations above the 75th percentile at delivery had a significantly increased risk of preeclampsia (odds ratio, 22.5 [95% CI, 1.8–279.9]). In conclusion, high circulating levels of s(P)RR at early pregnancy predicted a subsequent elevation in BP, and high concentrations at delivery were significantly associated with preeclampsia.