α-Lipoic acid exerts a primary prevention for the cardiac dysfunction in aortocaval fistula-created rat hearts.

AIM: α-Lipoic acid exerts a powerful antioxidant effect by acting as a free radical scavenger and inducing endogenous antioxidants such as vitamin E and glutathione. In the present study, we examined the effects of α-lipoic acid on cardiac dysfunction in rat hearts with aortocaval fistulae. MAIN METHODS: Aortocaval fistulae were created between the abdominal aorta and inferior vena cava in male rats. Hemodynamic parameters were measured 14 days after surgery using an intravascular pressure transducer, and then these hearts were harvested for tissue weight measurement, pathological evaluation, and mRNA isolation. RESULTS: In vehicle-treated rats, left ventricular end-diastolic pressure and left ventricular weight significantly increased at 14 days after fistula creation. Fistula-creation resulted in expression of 4-hydroxy-2-nonenal, NADPH oxidase subunit p67phox and BNP mRNA in a time-dependent manner in the left ventricle.Long-term treatment (initiated 2 days before surgery, and continued for 14 days after fistula creation; days -2 to 14) with α-lipoic acid (30 mg/kg/day) markedly suppressed the increases in left and right ventricular weight, and left ventricular end-diastolic pressure. α-Lipoic acid treatment from days -2 to 14 prominently prevented the expression of 4-hydroxy-2-nonenal and NADPH oxidase subunit p67phox, and significantly raised BNP mRNA levels. Short-term treatment with α-lipoic acid from day - 2 to 7 was effective in preventing cardiac enlargement and dysfunction, similar to long-term treatment, but treatment from days 7-14 was not effective. CONCLUSIONS: Treatment with α-lipoic acid can prevent cardiac hyperplasia and dysfunction, probably by inhibiting superoxide production and enhancing BNP mRNA expression in an early phase after fistula creation.

Integrated analysis of energy transfers in elastic-wave turbulence.

In elastic-wave turbulence, strong turbulence appears in small wave numbers while weak turbulence does in large wave numbers. Energy transfers in the coexistence of these turbulent states are numerically investigated in both the Fourier space and the real space. An analytical expression of a detailed energy balance reveals from which mode to which mode energy is transferred in the triad interaction. Stretching energy excited by external force is transferred nonlocally and intermittently to large wave numbers as the kinetic energy in the strong turbulence. In the weak turbulence, the resonant interactions according to the weak turbulence theory produce cascading net energy transfer to large wave numbers. Because the system's nonlinearity shows strong temporal intermittency, the energy transfers are investigated at active and moderate phases separately. The nonlocal interactions in the Fourier space are characterized by the intermittent bundles of fibrous structures in the real space.

Identification of a separation wave number between weak and strong turbulence spectra for a vibrating plate.

A weakly nonlinear spectrum and a strongly nonlinear spectrum coexist in a statistically steady state of elastic wave turbulence. The analytical representation of the nonlinear frequency is obtained by evaluating the extended self-nonlinear interactions. The critical wave numbers at which the nonlinear frequencies are comparable with the linear frequencies agree with the separation wave numbers between the weak and strong turbulence spectra. We also confirm the validity of our analytical representation of the separation wave numbers through comparison with the results of direct numerical simulations by changing the material parameters of a vibrating plate.

Bio-imaging of hydroxyl radicals in plant cells using the fluorescent molecular probe rhodamine B hydrazide, without any pretreatment.

Rhodamine B hydrazide can be used to detect hydroxyl radicals in plant cells. RBH was easily inserted into plant cells without any pretreatment, and specifically reacted with intracellular hydroxyl radicals produced by antimycin A. RBH will be a powerful tool for detecting hydroxyl radicals in plant cells.

Prolyl oligopeptidase inhibition-induced growth arrest of human gastric cancer cells.

Prolyl oligopeptidase (POP) is a serine endopeptidase that hydrolyzes post-proline peptide bonds in peptides that are <30 amino acids in length. We recently reported that POP inhibition suppressed the growth of human neuroblastoma cells. The growth suppression was associated with pronounced G0/G1 cell cycle arrest and increased levels of the CDK inhibitor p27(kip1) and the tumor suppressor p53. In this study, we investigated the mechanism of POP inhibition-induced cell growth arrest using a human gastric cancer cell line, KATO III cells, which had a p53 gene deletion. POP specific inhibitors, 3-({4-[2-(E)-styrylphenoxy]butanoyl}-l-4-hydroxyprolyl)-thiazolidine (SUAM-14746) and benzyloxycarbonyl-thioprolyl-thioprolinal, or RNAi-mediated POP knockdown inhibited the growth of KATO III cells irrespective of their p53 status. SUAM-14746-induced growth inhibition was associated with G0/G1 cell cycle phase arrest and increased levels of p27(kip1) in the nuclei and the pRb2/p130 protein expression. Moreover, SUAM-14746-mediated cell cycle arrest of KATO III cells was associated with an increase in the quiescent G0 state, defined by low level staining for the proliferation marker, Ki-67. These results indicate that POP may be a positive regulator of cell cycle progression by regulating the exit from and/or reentry into the cell cycle by KATO III cells.

Single-wave-number representation of nonlinear energy spectrum in elastic-wave turbulence of the Föppl-von Kármán equation: energy decomposition analysis and energy budget.

A single-wave-number representation of a nonlinear energy spectrum, i.e., a stretching-energy spectrum, is found in elastic-wave turbulence governed by the Föppl-von Kármán (FvK) equation. The representation enables energy decomposition analysis in the wave-number space and analytical expressions of detailed energy budgets in the nonlinear interactions. We numerically solved the FvK equation and observed the following facts. Kinetic energy and bending energy are comparable with each other at large wave numbers as the weak turbulence theory suggests. On the other hand, stretching energy is larger than the bending energy at small wave numbers, i.e., the nonlinearity is relatively strong. The strong correlation between a mode a(k) and its companion mode a(-k) is observed at the small wave numbers. The energy is input into the wave field through stretching-energy transfer at the small wave numbers, and dissipated through the quartic part of kinetic-energy transfer at the large wave numbers. Total-energy flux consistent with energy conservation is calculated directly by using the analytical expression of the total-energy transfer, and the forward energy cascade is observed clearly.

Oligomycin, an F1Fo-ATPase inhibitor, protects against ischemic acute kidney injury in male but not in female rats.

We investigated the effects of oligomycin, an F1Fo-ATPase inhibitor, on ischemic acute kidney injury in male and female rats. Ischemic acute kidney injury was induced by clamping the left renal artery and vein for 45 or 60 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal dysfunction and histological renal damage were observed 1 day after reperfusion in both male and female rats, although these renal injuries were more marked in male rats than in female rats. Intravenous bolus injection of oligomycin (0.5 mg/kg) 5 min before ischemia markedly attenuated the ischemia/reperfusion-induced renal injury in male rats. However, oligomycin did not show the protective effect in female rats subjected to ischemia/reperfusion-induced renal injury. Pre-ischemic treatment with oligomycin suppressed partly but significantly ischemia-induced renal ATP depletion only in male rats. These results indicate that oligomycin prevents the onset of ischemic acute kidney injury in male but not in female rats, and the effect is accompanied by suppression of the ATP depletion only in the male rat kidney during ischemia, thereby suggesting that the ATP hydrolysis pathway by mitochondrial F1Fo-ATPase induces a sex difference in ischemic acute kidney injury.

Protective effect of moxonidine on ischemia/reperfusion-induced acute kidney injury through α2/imidazoline I1 receptor.

Enhancement of renal sympathetic nerve activity during renal ischemia and norepinephrine overflow from the kidney after reperfusion play important roles in the development of ischemic acute kidney injury. Recently, we have found that moxonidine, an α2/imidazoline Ι1-receptor agonist, has preventive effects on ischemic acute kidney injury by suppressing the excitation of renal sympathetic nervous system after reperfusion. In the present study, to clarify the renoprotective mechanisms of moxonidine (360 nmol/kg, i.v.) against ischemic acute kidney injury, we investigated the effect of intravenous (i.v.) and intracerebroventricular (i.c.v.) injection of efaroxan, an α2/Ι1 receptor antagonist, on the moxonidine-exhibited actions. Ischemic acute kidney injury was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. The suppressive effect of moxonidine on enhanced renal sympathetic nerve activity during renal ischemia was not observed in the rat treated with either i.v. (360 nmol/kg) or i.c.v. (36 nmol/kg) of efaroxan. Furthermore, i.v. injection of efaroxan eliminated the preventive effect of moxonidine on ischemia/reperfusion-induced kidney injury and norepinephrine overflow, and i.c.v. injection of efaroxan did not completely inhibit the moxonidine's effects. These results indicate that moxonidine prevents the ischemic kidney injury by sympathoinhibitory effect probably via α2/Ι1 receptors in central nervous system and by suppressing the norepinephrine overflow through α2/Ι1 receptors on sympathetic nerve endings.

Sex differences in ischemia/reperfusion-induced acute kidney injury are dependent on the renal sympathetic nervous system.

Resistance to ischemic acute kidney injury has been shown to be higher in female rats than in male rats. We found that renal venous norepinephrine overflow after reperfusion played important roles in the development of ischemic acute kidney injury. In the present study, we investigated whether sex differences in the pathogenesis of ischemic acute kidney injury were derived from the renal sympathetic nervous system using male and female Sprague-Dawley rats. Ischemia/reperfusion-induced acute kidney injury was achieved by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function was impaired after reperfusion in both male and female rats; however, renal dysfunction and histological damage were more severe in male rats than in female rats. Renal venous plasma norepinephrine levels after reperfusion were markedly elevated in male rats, but were not in female rats. These sex differences were eliminated by ovariectomy or treatment with tamoxifen, an estrogen receptor antagonist, in female rats. Furthermore, an intravenous injection of hexamethonium (25mg/kg), a ganglionic blocker, 5 min before ischemia suppressed the elevation in renal venous plasma norepinephrine levels after reperfusion, and attenuated renal dysfunction and histological damage in male rats, and ovariectomized and tamoxifen-treated female rats, but not in intact females. Thus, the present findings confirmed sex differences in the pathogenesis of ischemic acute kidney injury, and showed that the attenuation of ischemia/reperfusion-induced acute kidney injury observed in intact female rats may be dependent on depressing the renal sympathetic nervous system with endogenous estrogen.

Weak and strong wave turbulence spectra for elastic thin plate.

A variety of statistically steady energy spectra in elastic wave turbulence have been reported in numerical simulations, experiments, and theoretical studies. Focusing on the energy levels of the system, we perform direct numerical simulations according to the Föppl-von Kármán equation, and successfully reproduce the variability of the energy spectra by changing the magnitude of external force systematically. When the total energies in wave fields are small, the energy spectra are close to a statistically steady solution of the kinetic equation in the weak turbulence theory. On the other hand, in large-energy wave fields, another self-similar spectrum is found. The coexistence of the weakly nonlinear spectrum in large wave numbers and the strongly nonlinear spectrum in small wave numbers is also found in moderate energy wave fields.

Large-scale lognormality in turbulence modeled by the Ornstein-Uhlenbeck process.

Lognormality was found experimentally for coarse-grained squared turbulence velocity and velocity increment when the coarsening scale is comparable to the correlation scale of the velocity [Mouri et al., Phys. Fluids 21, 065107 (2009)]. We investigate this large-scale lognormality by using a simple stochastic process with correlation, the Ornstein-Uhlenbeck (OU) process. It is shown that the OU process has a similar large-scale lognormality, which is studied numerically and analytically.

Prolyl oligopeptidase is a glyceraldehyde-3-phosphate dehydrogenase-binding protein that regulates genotoxic stress-induced cell death.

Prolyl oligopeptidase is a serine protease that cleaves peptides shorter 30-mer at carboxyl side of an internal proline. This enzyme has been proposed to be involved in the maturation and degradation of peptide hormones and neuropeptides. However, conclusive results have not yet been reported, and the primary physiological role remains to be elucidated. Here, we describe the identification of a novel protein that interacts with prolyl oligopeptidase in a human neuroblastoma cell line NB-1. Using an affinity column with immobilized recombinant human prolyl oligopeptidase as ligand, we identified glyceraldehyde-3-phosphate dehydrogenase as a novel prolyl oligopeptidase binding protein in NB-1 cell extracts. The interaction between prolyl oligopeptidase and glyceraldehyde-3-phosphate dehydrogenase was confirmed by immunoprecipitation both in vitro and in vivo. To study the functional relevance of prolyl oligopeptidase-glyceraldehyde-3-phosphate dehydrogenase interactions, we investigated whether this interaction was involved in cytosine arabinoside-induced glyceraldehyde-3-phosphate dehydrogenase nuclear translocation and cell death. Prolyl oligopeptidase inhibitor, SUAM-14746, and prolyl oligopeptidase knockdown successfully inhibited glyceraldehyde-3-phosphate dehydrogenase translocation and promoted the survival of cytosine arabinoside-treated NB-1 cells. We also found that the interactions between prolyl oligopeptidase and glyceraldehyde-3-phosphate dehydrogenase in the cytoplasm but not in nuclei of NB-1 cell treated with cytosine arabinoside using an in situ proximity ligation assay. These results indicate that the interaction between prolyl oligopeptidase and glyceraldehyde-3-phosphate dehydrogenase is required for cytosine arabinoside-induced glyceraldehyde-3-phosphate dehydrogenase nuclear translocation and cell death. Therefore, the results of the present study demonstrate a novel function for prolyl oligopeptidase in cell death.

Protective effect of 17ß-estradiol on ischemic acute kidney injury through the renal sympathetic nervous system.

Enhanced renal sympathetic nerve activity during an ischemic period and renal venous norepinephrine overflow after reperfusion play important roles in the development of ischemic acute kidney injury. In this study, we examined the effect of 17ß-estradiol on the renal sympathetic nervous system and kidney function in ischemia/reperfusion-induced acute kidney injury in anesthetized rats. Ischemic acute kidney injury was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after a contralateral nephrectomy. Intravenous injection of 17ß-estradiol (100 µg/kg) 15 min before reperfusion suppressed enhanced renal sympathetic nerve activity during renal ischemia, also suppressed renal venous norepinephrine overflow after reperfusion, and attenuated ischemia/reperfusion-induced renal dysfunction with histological damage. The above renoprotective effects of 17ß-estradiol were reversed by pretreatment with tamoxifen (5 mg/kg), an estrogen receptor antagonist, or N(G)-nitro-L-arginine methyl ester (0.3 mg/kg), a non-selective nitric oxide synthase inhibitor. These results indicate that 17ß-estradiol can suppress enhanced renal sympathetic nerve activity during renal ischemia, and its consequent effect on norepinephrine overflow from nerve endings, by nitric oxide production via estrogen receptors. These effects appear to contribute to renoprotection against ischemia/reperfusion-induced renal injury.

Prolyl oligopeptidase participates in cell cycle progression in a human neuroblastoma cell line.

Prolyl oligopeptidase (POP) is a post-proline cleaving enzyme, which is widely distributed in various organs, with high levels in the brain. In this study, we investigated the effects of a selective POP inhibitor, 3-({4-[2-(E)-styrylphenoxy]butanoyl}-l-4-hydroxyprolyl)-thiazolidine (SUAM-14746), on the growth of NB-1 human neuroblastoma cells. SUAM-14746 treatment for 24-72 h suppresses the growth of NB-1 cells without cell death in a dose-dependent manner (10-60 µM). Similar suppressive effects were observed with another POP inhibitor benzyloxycarbonyl-thioprolyl-thioprolinal. The SUAM-14746-induced growth inhibition in NB-1 cells was associated with pronounced G(0)/G(1) arrest and reduced levels of phosphorylated retinoblastoma protein (pRb), cyclin E, and cyclin dependent kinase (CDK) 2, and increased levels of the CDK inhibitor p27(kip1) and the tumor suppressor p53. SUAM-14746 also induced transient inhibition of S and G(2)/M phase progression, which was correlated with retardation of the decrease in the levels of cyclins A and B. Moreover, RNAi-mediated knockdown of POP also led to inhibition of NB-1 cell growth and the effect was accompanied by G(0)/G(1) arrest. These results indicate that POP is a part of the machinery that controls the cell cycle.

Preventive effect of SA13353 [1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea], a novel transient receptor potential vanilloid 1 agonist, on ischemia/reperfusion-induced renal injury in rats.

Tumor necrosis factor (TNF)-alpha plays a crucial role in the pathogenesis of ischemia/reperfusion-induced renal injury. We demonstrated recently that the preischemic treatment with resiniferatoxin, a transient receptor potential vanilloid 1 (TRPV1) agonist, attenuates renal TNF-alpha mRNA expression and improves ischemia/reperfusion-induced renal injury in rats. In addition, we found that SA13353 [1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea], a novel orally active TRPV1 agonist, inhibits TNF-alpha production through the activation of capsaicin-sensitive afferent neurons and reduces the severity of symptoms in established rat collagen-induced arthritis. In the present study, we investigated effects of treatment with SA13353 on ischemia/reperfusion-induced renal injury in rats. Ischemic acute kidney injury (AKI) 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 vehicle-treated AKI rats markedly decreased at 24 h after reperfusion. Treatment with SA13353 (3, 10, and 30 mg/kg p.o.) 30 min before ischemia dose-dependently attenuated the ischemia/reperfusion-induced renal dysfunction. Histopathological examination of the kidney of AKI rats revealed severe renal damage, which were significantly suppressed by the SA13353 treatment. In renal tissues exposed to ischemia/reperfusion, neutrophil infiltration, superoxide production, TNF-alpha mRNA expression, and cytokine-induced neutrophil chemoattractant-1 mRNA expression were augmented, but these alterations were attenuated by the treatment with SA13353. On the other hand, ischemia/reperfusion-enhanced renal interleukin-10 mRNA expression and its plasma concentration were further augmented by SA13353 treatment. These results demonstrate that the orally active TRPV1 agonist SA13353 prevents the ischemia/reperfusion-induced AKI. This renoprotective effects seem to be closely related to the inhibition of inflammatory response via TRPV1 activation.

Drug discovery for overcoming chronic kidney disease (CKD): the endothelin ET B receptor/nitric oxide system functions as a protective factor in CKD.

Accelerated cardiovascular disease (CVD) is a frequent complication of renal disease. Chronic kidney disease (CKD) develops hypertension and dyslipidemia, which in turn can contribute to the progression of renal failure. There is general agreement that endothelin-1 (ET-1), which acts through the two subtypes of receptor ET(A) and ET(B), plays important physiological roles in the regulation of normal cardiovascular function and that excessive ET-1 production is linked to CVD and CKD. Although selective ET(A) or nonselective ET(A)/ET(B) receptor antagonisms have been recognized as a potential strategy for treatment of several cardiovascular disease, it remains unclear which of the antagonisms is suitable for the individuals with CKD because upregulation of the nitric oxide (NO) system via ET(B) receptor is responsible for renal function such as natriuresis, diuresis, and glomerular hemodynamics. Our findings clearly indicate that the blockade of ET receptors, in particular ET(A)-receptor antagonism, not only produces a potential renoprotective effect in CKD but also reduces the risk of CVD. In contrast, pharmacological blockade or genetic deficiency of ET(B) receptor seems to aggravate CKD and CVD in several experimental models of rats. Moreover, preliminary evidence in patients with CKD also suggests that both selective ET(A)- and nonselective ET(A)/ET(B)-receptor blockade decreases blood pressure but that selective ET(A) blockade has additional desirable effects on renal hemodynamics. Thus, at least in CKD, these findings support the notion that ET(B) receptor-mediated actions produce a renoprotective effect and that nonselective ET(A)/ET(B)-receptors blockade seem to offer no advantage over selective ET(A) antagonism, and if anything may potentially reduce the benefits.

Moxonidine prevents ischemia/reperfusion-induced renal injury in rats.

Enhancement of renal sympathetic nerve activity during renal ischemia and its consequent effect on norepinephrine overflow from nerve endings after reperfusion play important roles in the development of ischemic acute kidney injury. In the present study, we evaluated whether moxonidine, an alpha(2)-adrenaline/I(1)-imidazoline receptor agonist which is known to elicit sympathoinhibitory action, would prevent the post-ischemic renal injury. Ischemic acute kidney injury was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Intravenous (i.v.) injection of moxonidine at a dose of 360 nmol/kg to ischemic acute kidney injury rats suppressed the enhanced renal sympathetic nerve activity during the ischemic period, to a degree similar to findings with intracerebroventricular (i.c.v.) injection of moxonidine at a dose of 36 nmol/kg. On the other hand, suppressive effects of the i.v. treatment on renal venous norepinephrine overflow, renal dysfunction and tissue injury in the post-ischemic kidney were significantly greater than those elicited by the i.c.v. treatment. These results suggest that renoprotective effects of moxonidine on ischemic acute kidney injury probably result from its suppressive action on the ischemia-enhanced renal sympathetic nerve activity followed by norepinephrine spillover from the nerve endings of the post-ischemic kidney.

Preventive mechanisms of agmatine against ischemic acute kidney injury in rats.

The excitation of renal sympathetic nervous system plays an important role in the development of ischemic acute kidney injury in rats. Recently, we found that agmatine, an adrenaline alpha(2)/imidazoline I(1)-receptor agonist, has preventive effects on ischemic acute kidney injury by suppressing the enhanced renal sympathetic nerve activity during renal ischemia and by decreasing the renal venous norepinephrine overflow after reperfusion. In the present study, we investigated preventive mechanisms of agmatine against ischemic acute kidney injury in rats. Ischemic acute kidney injury was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after the contralateral nephrectomy. Pretreatment with efaroxan (30 mumol/kg, i.v.), an alpha(2)/I(1)-receptor antagonist, abolished the suppressive effects of agmatine on the enhanced renal sympathetic nerve activity during renal ischemia and on the elevated norepinephrine overflow after reperfusion, and eliminated the preventing effects of agmatine on the ischemia/reperfusion-induced renal dysfunction and histological damage. On the other hand, pretreatment with yohimbine (6 mumol/kg, i.v.), an alpha(2)-receptor antagonist, eliminated the preventing effects of agmatine on the ischemia/reperfusion-induced renal injury and norepinephrine overflow, without affecting the lowering effect of agmatine on renal sympathetic nerve activity. These results indicate that agmatine prevents the ischemic renal injury by sympathoinhibitory effect probably via I(1) receptors in central nervous system and by suppressing the norepinephrine overflow through alpha(2) or I(1) receptors on sympathetic nerve endings.

Angiotensin II type 2 receptor-mediated inhibition of norepinephrine release in isolated rat hearts.

We investigated whether endogenous and exogenous angiotensin II (Ang II) regulates norepinephrine (NE) release from cardiac sympathetic nerves via both Ang II type 2 receptors (AT2Rs) and Ang II type 1 receptors (AT1Rs). Using isolated rat hearts, sympathetic nerves were electrically stimulated. Ang II with PD-123319 (AT2R antagonist) but not Ang II alone produced a significant increase in nerve stimulation-induced NE overflow, which was abolished by the addition of AT1R antagonist losartan. In contrast, NE overflow was markedly decreased by losartan with or without Ang II. This decrease was abolished by the combination with PD-123319, nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine (NOARG), icatibant (bradykinin B2 receptor antagonist), or PKSI-527 (kininogenase inhibitor). CGP-42112A (AT2R agonist) suppressed nerve stimulation-induced NE overflow in the same way as the combination of Ang II and losartan, and this suppression was abolished by PD-123319, NOARG, icatibant, or PKSI-527. There were significant increases in NOx (NO2/NO3) contents in coronary effluent under conditions where NE overflow was suppressed. Ang II seems to function as an inhibitory modulator of cardiac noradrenergic neurotransmission via AT2Rs and well-known AT1R-mediated stimulatory actions. The inhibitory mechanism may involve local bradykinin production, its B2 receptor activation, and NO as a downstream effector.

Preventive effect of TRPV1 agonists capsaicin and resiniferatoxin on ischemia/reperfusion-induced renal injury in rats.

We evaluated the effect of capsaicin, one of the transient receptor potential vanilloid receptor 1 (TRPV1) agonists, on ischemic acute renal failure (ARF) in rats. Ischemic ARF was induced by occlusion of the left renal artery and vein for 45 minutes followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function in vehicle-treated ARF rats markedly decreased at 24 hours after reperfusion. Treatment with capsaicin (3, 10, and 30 mg/kg, orally) 30 minutes before ischemia dose-dependently attenuated ischemia/reperfusion-induced renal dysfunction. In renal tissues exposed to ischemia/reperfusion, neutrophil infiltration, renal superoxide production, and renal tumor necrosis factor (TNF)-alpha mRNA expression were augmented, but these alterations were attenuated by the treatment with capsaicin. On the other hand, ischemia/reperfusion-enhanced renal interleukin (IL)-10 mRNA expression and plasma concentrations of IL-10 were augmented by treatment with capsaicin in ARF rats. In addition, resiniferatoxin (20 microg/kg, subcutaneous), a more selective and potent TRPV1 agonist, showed a renoprotective effect on ischemia/reperfusion-induced renal injury, in a qualitatively similar way to cases seen with capsaicin. These results demonstrate that TRPV1 agonists prevent ischemia/reperfusion-induced renal dysfunction. These renoprotective effects seem to be closely related to the inhibition of inflammatory response via TRPV1.