- Email: [email protected]
Up-regulation of renal endothelial and inducible nitric oxide synthase in obstructive nephropathy.
52A
AJH-APRIL 1999-VOL. 12, NO. 4, PART 2
ASH XIV ABSTRACTS
D013
D014
Interactions between Endothelin-1 and the Renin-AngiotensinAldosterone system (RAAS) G.P. Rossi, A. Sacehetto, M. Cesari, G.G. Nussdorfer* & A. C. Pessina. Depts of Clinical & Experimental Medicine & * Anatomy & Physiology, University of Padova, Italy. The RAAS and the endothelins system (ETs) entail the most potent vasopressor mechanisms identified as yet. Although they wore studied in depth in relation to arterial hypertension and cardiovascular diseases, little information on their relationships exist. The identification of consensus sequences forjun in the regulatory region of the prcproendothelin-1 (ppET-l) gene suggested its transcriptional regulation by factors acting through the PKC and PLC pathway. In fact, angiotensin II (Ang If) induced expression of the ppET-I gene and synthesis of ET-1 in cultured vascular smooth muscle (VSMC), endothelial cells, and cardiomyocytes, thereby suggesting a role of the pcptidc in cardiovascular remodeling. Furthermore, ET-I exerts multifaceted effects on the RAAS, such as dose-dependently inhibiting renin synthesis, and stimulating aldosterone secretion. We found with autoradiography abundant specific ET-1 receptors in the human adrenocortical zona glomemlosa (ZG) and thus suggested a direct secrctagogue effect of ET-1. In rats ETB receptors mediated such effect, whilst in humans both receptor subtypes intervened in regulating the trascription of the aldosterone synthase gene.ln in vitro human adrenocortical ZG cells and in Coan's adenoma cells, ET-1 was found to be equipotent to Ang ]I. Additionally, ET-l stimulates DNA synthesis and proliferation of ZG cells via ETA receptors. These effects were dose-dependently blunted by either Ro31-8220 or tyrphostin-23, and thus involve activation of both the PKC and the tyrosin-kinase signalling pathways. Collectively our findings show that ET-1 potently stimulates aldosterone secretion and adrenocortical growth. The latter effect is likely to occur on the "cambium" layer of ceils endowed with ETA receptors, which are mainly located in the ZG. Key Words: Angiotensin, endothelins, hypertension, renin angiotensin system, receptors
UP-REGULATION OF RENAL ENDOTHELIAL AND INDUCIBLE NITRIC OXIDE SYNTHASE IN OBSTRUCTIVE NEPHROPATHY. Z-Q Wang, HM Siragy, RL Chevalier, RM Carey*. University of Virginia Health Sciences Center, Chadottesville, VA. Nitdc oxide (NO) plays a cdtical role in the control of naurotransmission, vascular tone, apoptosis and inflammation. Basal NO production in the kidney regulates renal hemodynamics, tubuloglomerular feedback, renin release and extracellular fluid volume. Inhibition of NO synthase (NOS) with NG-nitro-L-arginine methyl ester aggravates renal vasoconstriction and kidney tissue damage in the hydronephrotic kidney. However, the expression of renal NOS in obstructive nephropathy remains unknown. In the present study, regulation of renal endothelial (eNOS) and inducible (iNOS) NOS was investigated in adult rats subject to acute (2-day, n=6) or chronic (2-week, n=3) complete unilateral ureteral obstruction (CUUO). The concentration of renal venous total nitrate/nitrite from the obstructed kidney (OK) was significantly higher than from the unobstructed contralateral kidney (CK) in acute CUUO (29.95:3.1 vs. 21.7_+4.1 i~1, P
D015
D016
IN VIVO EXPERIMENTS OF r H u E P O - - D E R I V E D HYPERTENSION. S Nakamura, K Nakayama, CL Yang , and T Aoki. Aichi Medical University,
~'~T
Nagakute Aichi, ,.Japan The etiology of "t" HuEPO--derived
Kakumu.
hypertension has not completely been clarified. Experiments using rabbits were undertaken to elucidate in vivo if endothelin-- 1 l E T - - 1 ) would be involved in 7'HuEPO--derived hypertension. Blood pressure increased significantly from 124. 5 / 7 7 . 0-1-14. 6 / 1 6 . 0 mmH~, to 130. 0 / B O . 2-t-21. 0 / 1 3 . 3 m m H g ( p < O . 05) 5 minutes after intravenous injection of "yHuEPO
In vitro experiments have shown that angiotensin I] (A ]l) stimulates, nitric oxide (NO)
( 1 0 0 0 u / k g ) , while plasma ET--1 level also elevated significantly from 15. 7-1-3. 6 pmoles / m l to 19. 0 + 4 . 9 p m o l e s / m l (p
OF A I ~ O T B ~ I N
lI AND N O ~ I N E
ON NITRIC OXIDE IN THE R ~ B n " KIDNEY.
S Nakamura, K Nakayama, CL Yang, T Aoki and S Aichi Medical University, Nagakute, Aichi,
Japan.
release in the isolated artery. The present study was performed to evaluate the changes in blood pressure (BP) and NO when A ]I or noradrenaline (NA) was intravenously given into rabbits. NO was measured at the renal cortex via inserting a NOsensitive electrode. BP increased significantly 1 minute after A ]I (5 /~ g/kg) injection and 0.5 min. after NA (3 /z g/kg) injection
(p <0.05). Moreover,
significant increase in NO current was detected 92.4 pA (1.8X10TM for NO) after A ]] injection, in contrast to 190.6 p A ( 4 . 3 X l 0 T M for NO) in case of NA administration (p <0.05). In conclusion possible vascular contractions with resultant increment in BP may be involved in NO release.
KeyWords:
nitricoxide, noradrenaline, angiotensin [|, NO-sensitiveelectrode
AJH-APRIL 1999-VOL. 12, NO. 4, PART 2
ASH XIV ABSTRACTS
D013
D014
Interactions between Endothelin-1 and the Renin-AngiotensinAldosterone system (RAAS) G.P. Rossi, A. Sacehetto, M. Cesari, G.G. Nussdorfer* & A. C. Pessina. Depts of Clinical & Experimental Medicine & * Anatomy & Physiology, University of Padova, Italy. The RAAS and the endothelins system (ETs) entail the most potent vasopressor mechanisms identified as yet. Although they wore studied in depth in relation to arterial hypertension and cardiovascular diseases, little information on their relationships exist. The identification of consensus sequences forjun in the regulatory region of the prcproendothelin-1 (ppET-l) gene suggested its transcriptional regulation by factors acting through the PKC and PLC pathway. In fact, angiotensin II (Ang If) induced expression of the ppET-I gene and synthesis of ET-1 in cultured vascular smooth muscle (VSMC), endothelial cells, and cardiomyocytes, thereby suggesting a role of the pcptidc in cardiovascular remodeling. Furthermore, ET-I exerts multifaceted effects on the RAAS, such as dose-dependently inhibiting renin synthesis, and stimulating aldosterone secretion. We found with autoradiography abundant specific ET-1 receptors in the human adrenocortical zona glomemlosa (ZG) and thus suggested a direct secrctagogue effect of ET-1. In rats ETB receptors mediated such effect, whilst in humans both receptor subtypes intervened in regulating the trascription of the aldosterone synthase gene.ln in vitro human adrenocortical ZG cells and in Coan's adenoma cells, ET-1 was found to be equipotent to Ang ]I. Additionally, ET-l stimulates DNA synthesis and proliferation of ZG cells via ETA receptors. These effects were dose-dependently blunted by either Ro31-8220 or tyrphostin-23, and thus involve activation of both the PKC and the tyrosin-kinase signalling pathways. Collectively our findings show that ET-1 potently stimulates aldosterone secretion and adrenocortical growth. The latter effect is likely to occur on the "cambium" layer of ceils endowed with ETA receptors, which are mainly located in the ZG. Key Words: Angiotensin, endothelins, hypertension, renin angiotensin system, receptors
UP-REGULATION OF RENAL ENDOTHELIAL AND INDUCIBLE NITRIC OXIDE SYNTHASE IN OBSTRUCTIVE NEPHROPATHY. Z-Q Wang, HM Siragy, RL Chevalier, RM Carey*. University of Virginia Health Sciences Center, Chadottesville, VA. Nitdc oxide (NO) plays a cdtical role in the control of naurotransmission, vascular tone, apoptosis and inflammation. Basal NO production in the kidney regulates renal hemodynamics, tubuloglomerular feedback, renin release and extracellular fluid volume. Inhibition of NO synthase (NOS) with NG-nitro-L-arginine methyl ester aggravates renal vasoconstriction and kidney tissue damage in the hydronephrotic kidney. However, the expression of renal NOS in obstructive nephropathy remains unknown. In the present study, regulation of renal endothelial (eNOS) and inducible (iNOS) NOS was investigated in adult rats subject to acute (2-day, n=6) or chronic (2-week, n=3) complete unilateral ureteral obstruction (CUUO). The concentration of renal venous total nitrate/nitrite from the obstructed kidney (OK) was significantly higher than from the unobstructed contralateral kidney (CK) in acute CUUO (29.95:3.1 vs. 21.7_+4.1 i~1, P
D015
D016
IN VIVO EXPERIMENTS OF r H u E P O - - D E R I V E D HYPERTENSION. S Nakamura, K Nakayama, CL Yang , and T Aoki. Aichi Medical University,
~'~T
Nagakute Aichi, ,.Japan The etiology of "t" HuEPO--derived
Kakumu.
hypertension has not completely been clarified. Experiments using rabbits were undertaken to elucidate in vivo if endothelin-- 1 l E T - - 1 ) would be involved in 7'HuEPO--derived hypertension. Blood pressure increased significantly from 124. 5 / 7 7 . 0-1-14. 6 / 1 6 . 0 mmH~, to 130. 0 / B O . 2-t-21. 0 / 1 3 . 3 m m H g ( p < O . 05) 5 minutes after intravenous injection of "yHuEPO
In vitro experiments have shown that angiotensin I] (A ]l) stimulates, nitric oxide (NO)
( 1 0 0 0 u / k g ) , while plasma ET--1 level also elevated significantly from 15. 7-1-3. 6 pmoles / m l to 19. 0 + 4 . 9 p m o l e s / m l (p
OF A I ~ O T B ~ I N
lI AND N O ~ I N E
ON NITRIC OXIDE IN THE R ~ B n " KIDNEY.
S Nakamura, K Nakayama, CL Yang, T Aoki and S Aichi Medical University, Nagakute, Aichi,
Japan.
release in the isolated artery. The present study was performed to evaluate the changes in blood pressure (BP) and NO when A ]I or noradrenaline (NA) was intravenously given into rabbits. NO was measured at the renal cortex via inserting a NOsensitive electrode. BP increased significantly 1 minute after A ]I (5 /~ g/kg) injection and 0.5 min. after NA (3 /z g/kg) injection
(p <0.05). Moreover,
significant increase in NO current was detected 92.4 pA (1.8X10TM for NO) after A ]] injection, in contrast to 190.6 p A ( 4 . 3 X l 0 T M for NO) in case of NA administration (p <0.05). In conclusion possible vascular contractions with resultant increment in BP may be involved in NO release.
KeyWords:
nitricoxide, noradrenaline, angiotensin [|, NO-sensitiveelectrode