Yasuo Matsumura

Role of nitric oxide in the renal protective effects of ischemic preconditioning.

&NA; Possible involvement of nitric oxide (NO) in the protective effect of ischemic preconditioning against the ischemia/reperfusion‐induced acute renal failure was investigated. Ischemic preconditioning, which consists of three cycles of 2‐minute ischemia followed by 5‐minute reperfusion, was performed prior to 45‐minute ischemia. Ischemic preconditioning significantly improved the renal dysfunction induced by 45‐minute ischemia followed by 24‐hour reperfusion. Histopathological examination of the kidney of ischemia/reperfusion rats revealed severe renal damage, and suppression of the damage was seen with the ischemic preconditioning treatment. NO metabolites (NOx) production in the kidney after 45‐minute ischemia and reperfusion was markedly increased in ischemia/reperfusion rats with ischemic preconditioning, compared with animals not subjected to ischemic preconditioning, and these increases correlated with changes in endothelial NO synthase (eNOS) protein expression in renal tissues. The improvement of renal dysfunction in ischemic preconditioning rats was abolished by the pretreatment with NG‐nitro‐L‐arginine, a nonselective NOS inhibitor, but not with aminoguanidine, an inducible NOS inhibitor. In addition, increment of endothelin‐1 (ET‐1) content in the kidney after the reperfusion was markedly suppressed by ischemic preconditioning treatment. These findings suggest that the protective effect of ischemic preconditioning on ischemia/reperfusion ‐induced acute renal failure is closely related to the renal nitric oxide production following the increase in eNOS expression after the reperfusion and that the suppressive effect of ischemic preconditioning on the ischemia/reperfusion ‐induced renal ET‐1 overproduction may be partly involved in the ameliorating effect of ischemic preconditioning.

Protective Effect Of α-LIPOIC Acid Against Ischaemic Acute Renal Failure In Rats

1. In the present study, we investigated whether treatment with α‐lipoic acid (LA), a powerful and universal anti‐oxidant, has renal protective effects in rats with ischaemic acute renal failure (ARF).

Preventive effect of L-carnosine on ischemia/reperfusion-induced acute renal failure in rats

We investigated the effect of L-carnosine (beta-alanyl-L-histidine) on ischemic acute renal failure in rats. Ischemic acute renal failure was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function in untreated acute renal failure rats markedly decreased at 1 day after reperfusion. Pre-ischemic treatment with L-carnosine dose-dependently (1, 10 microg/kg, i.v.) attenuated the ischemia/reperfusion-induced renal dysfunction. Histopathological examination of the kidney of untreated acute renal failure rats revealed severe renal damage, which was significantly suppressed by pre-treatment with L-carnosine, at each dose given. In untreated acute renal failure rats, norepinephrine concentrations in renal venous plasma remarkably increased within 2 min after reperfusion and thereafter rapidly decreased. Pre-ischemic treatment with L-carnosine at a dose of 10 microg/kg significantly depressed the elevated norepinephrine level. On the other hand, although the higher dose of L-carnosine given 5 min after reperfusion tended to ameliorate the renal dysfunction after reperfusion, the improvement was moderate compared with those seen in pre-ischemic treatment. These results indicate that L-carnosine prevents the development of ischemia/reperfusion-induced renal injury, and the effect is accompanied by suppression of the enhanced norepinephrine release in the kidney immediately after reperfusion. Thus, the preventing effect of L-carnosine on ischemic acute renal failure is probably through the suppression of enhanced renal sympathetic nerve activity induced by ischemia/reperfusion.

Oestrogen protects against ischaemic acute renal failure in rats by suppressing renal endothelin-1 overproduction

We investigated whether the treatment with 17 beta-oestradiol has renal protective effects in male rats with ischaemic acute renal failure (ARF). We also examined if the effect of 17 beta-oestradiol is accompanied by suppression of enhanced endothelin-1 production in postischaemic kidneys. Ischaemic ARF was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function parameters such as blood urea nitrogen, plasma creatinine and creatinine clearance were measured to test the effectiveness of the steroid hormone. Renal function in ARF rats markedly decreased 24 h after reperfusion. The ischaemia/reperfusion-induced renal dysfunction was dose-dependently improved by pretreatment with 17 beta-oestradiol (20 or 100 microg/kg, intravenously). Histopathological examination of the kidney of untreated ARF rats revealed severe lesions, such as tubular necrosis, proteinaceous casts in tubuli and medullary congestion, all of which were markedly improved by the higher dose of 17 beta-oestradiol. In addition, endothelin-1 content in the kidney after the ischaemia/reperfusion increased significantly by approx. 2-fold over sham-operated rats, and this elevation was dose-dependently suppressed by the 17 beta-oestradiol treatment. These results suggest that oestrogen exhibits protective effects against renal dysfunction and tissue injury induced by ischaemia/reperfusion, possibly through the suppression of endothelin-1 overproduction in postischaemic kidneys.

Nitric oxide protects against ischemic acute renal failure through the suppression of renal endothelin-1 overproduction

To elucidate the role of nitric oxide in the pathogenesis of ischemic acute renal failure, we investigated the effects of FK409, a spontaneous nitric oxide donor, and NG-nitro-L-arginine methyl ester, a non-selective nitric oxide synthase inhibitor, on ischemia/reperfusion-induced renal injury and endothelin-1 overproduction in post-ischemic kidneys. Ischemic acute renal failure was induced by occlusion of the left renal artery and vein for 45 minutes followed by reperfusion, 2 weeks after contralateral nephrectomy. At 24 hours after reperfusion, renal function in untreated acute renal failure rats markedly decreased and histological examination revealed severe renal damage of the kidney. Increases in renal endothelin-1 contents were evident in the acute renal failure rats at 2 and 24 hours after reperfusion, respectively. Pretreatment with FK409 (1 or 3 mg/kg, intravenously) dose-dependently ameliorated renal injuries and suppressed the elevation of endothelin-1 content induced by ischemia/reperfusion. In contrast, NG-nitro-L-arginine methyl ester (1 or 10 mg/kg, intravenously) pretreatment dose-dependently aggravated renal injuries of acute renal failure rats, and the effect is accompanied by further increase in the renal endothelin-1 contents. These results suggest that both exogenous and endogenous nitric oxide have protective effects against ischemia/reperfusion-induced renal dysfunction and tissue damage, probably through the suppression of endothelin-1 overproduction in post-ischemic kidneys.

Pathophysiological Role of Proteasome-Dependent Proteolytic Pathway in Endothelin-1-Related Cardiovascular Diseases

A proteasome-dependent proteolytic pathway serves important functions in cell cycle control and transcriptional regulation; however, its pathophysiological role in cardiovascular diseases is still unclear. We have recently obtained evidence that proteasome inhibitors are capable of preventing the development of deoxycorticosterone acetate (DOCA)-salt-induced hypertension or hypertrophy and of ischemic acute renal failure (ARF). Beneficial effects of the proteasome inhibitors were accompanied by a decrease in endothelin-1 (ET-1) content in the aorta and kidney of DOCA-salt and ischemic ARF animals, respectively. In addition, there is evidence showing that the reduction of nuclear factor-kappaB (NF-kappaB) activation is involved in the mechanisms for suppressive effects of proteasome inhibitors on ET-1 gene transcription and the consequent decrease in ET-1 mRNA expression in the cultured vascular endothelial cells. These findings suggest that a proteasome-dependent proteolytic pathway has a crucial role in the pathogenesis of ET-1-related cardiovascular diseases, probably through the activation of NF-kappaB, and also that the use of proteasome inhibitors may be a novel approach to the treatment of cardiovascular diseases.

Role of endothelin B receptor in the pathogenesis of ischemic acute renal failure.

This study evaluated the role of endothelin B (ETB) receptor–mediated action in the development and maintenance of ischemic acute renal failure (ARF), using the spotting-lethal (sl) rat that carries a naturally occurring deletion in the ETB receptor gene. Because homozygous (sl/sl) rats die shortly after birth due to congenital distal intestinal aganglionosis, genetic rescue of sl/sl rats from the developmental defect using a dopamine-&bgr;-hydroxylase (D&bgr;H)-ETB transgene was performed to produce ETB-deficient adult rats. Rescued homozygous (D&bgr;H-ETBsl/sl) and wild-type (D&bgr;H-ETB +/+) rats were subjected to ischemic ARF by clamping the renal pedicle for 45 min followed by reperfusion. At 24 h after the reperfusion, renal glomerular dysfunction and histologic damage, such as proteinaceous casts in tubuli, were markedly and observed equally in homozygous and wild-type groups, and these renal injuries gradually recovered. However, when the ischemia/reperfusion-induced renal injury was examined 7 days after the reperfusion, the recovery in homozygous ARF rats was obviously delayed compared with the wild-type animals. Two of the eight homozygous ARF rats died within 3 days after the reperfusion. Increment of renal endothelin-1 content after the ischemia/reperfusion was more marked in homozygous than in wild-type rats. Thus, ETB receptor–mediated actions do not play an important role in the development of ischemic ARF but may be involved in the recovery process from ischemia/reperfusion-induced renal injury.