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Vitamin E was previously reported to reduce calcium oxalate (CaOx) crystal formation. This study explored whether vitamin E deficiency affects intrarenal oxidative stress and accelerates crystal deposition in hyperoxaluria. The control (C) group of rats received a standard diet and drinking water, while the experimental groups received 0.75% ethylene glycol (EG) in drinking water for 42 days. Of the latter, one group received a standard diet (EG group), one received a low-vitamin E (LE) diet (EG+LE group), and the last received an LE diet with vitamin E supplement (4 mg) (EG+LE+E group). The C+LE and C+LE+E groups were the specific controls for the last two experimental groups, respectively. In a separate experiment, EG and EG+LE rats were studied on days 3-42 to examine the temporal relationship between oxidative change and crystal formation. Urinary biochemistry and activity/levels of antioxidative and oxidative enzymes in glomeruli and tubulointerstitial specimens (TIS) were examined. In EG rats, CaOx crystal accumulation was associated with low antioxidative enzyme activity in TIS and with increased oxidative enzyme expression in glomeruli. In the EG+LE group, marked changes in antioxidative and oxidative enzyme levels were seen and correlated with massive CaOx deposition and tubular damage. The increased oxidative stress seen with EG+LE treatment was largely reversed by vitamin E supplementation. A temporal study showed that decrease in antioxidative defense and increased free radical formation in the EG+LE group occurred before crystal deposition. This study shows that low vitamin E disrupts the redox balance and causes cell death, thereby favoring crystal formation. antioxidative proteins; free radicals; hyperoxaluria

Hyperoxaluric kidneys show an impaired diuretic response to acute infusion of L-arginine. In this study, we examined the chronic effect of L-arginine supplementation on CaOx crystal formation in hyperoxaluric rat kidneys. Eight groups were tested: control (received drinking water), L group (received L-arginine, 0.6%), LN group [received [N.sup.G]-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg)], L + LN group (received L-arginine + L-NAME), HP group [received hydroxyl-L-proline (HP, 5%) mixed with chow to induce hyperoxaluria], L + HP group (received HP + t.-arginine), HP + LN group, and L + HP + LN group. The duration was 42 days, and each group had eight animals. Urinary biochemistry and renal CaOx amounts were measured, as well as renal expressions of nitric oxide synthase (NOS) isoforms and NAD(P)H oxidase. The distribution of inducible NOS (iNOS), NAD(P)H oxidase, ED1-positive cells, and nitrotyrosine was examined by immunohistochemical and immunofluorescence studies, whereas superoxide production from the kidneys was examined by fluorescence spectrometric assay. Compared with the HP group, the L + HP group had excessive CaOx crystal accumulation and enhanced endothelial NOS (eNOS), iNOS, and NAD(P)H oxidase protein expression in the kidney. Urinary excretion of nitrotyrosine was markedly increased. Increased superoxide formation in the L + HP kidney was derived from NAD(P)H oxidase and uncoupled eNOS, and increased nitrotyrosine formation might derive from iNOS and EDl-positive cells that gathered around the CaOx crystals. L-NAME cotreatment (L + HP + LN group) reduced renal oxidative nitrosative stress and tubular damage, which were induced by L + HP. The results showed that chronic L-arginine treatment to the hyperoxaluric kidney with massive CaOx crystal deposition may have a toxic effect by enhancing intrarenal oxidative and nitrosative stress. hyperoxaluria; nephrolithiasis; NAD(P)H oxidase; nitric oxide synthase

N-methyl-D-aspartate (NMDA) receptor activated by glutamate/glycine is located in the kidneys. The NMDA receptor subunit NRI is increased in damaged renal tissue. This study explored the role of NMDA receptors in ischemia-reperfusion-induced renal dysfunction in rats. With Western blot analysis and renal functional assay, NMDA receptor expression was evaluated, as well as its functional role in female Wistar rat kidneys after 45 min of unilateral ischemia followed by 24 h of reperfusion. The effects of intrarenal NMDA receptor agonist and antagonist on renal blood flow (RBF), glomerular filtration rate (GFR), urine volume (UV), sodium (UNaV), and potassium (UKV) excretion were determined. NMDA NR1 was present in the glomeruli, brush-border membrane, and outer medulla but not in the cortex and inner medulla. Homogenous distribution of non-NMDA GluR2/3, sparse kainate KAI, and undetectable group I of metabotropic glutamate receptor were noted in the control kidneys. Ischemia-reperfusion kidneys showed enhanced renal NR1, but not NR2C and GluR2/3 expression, and were associated with decreased GFR/RBF and natriuretic/diuretic responses. Intrarenal NMDA agonists significantly reduced GFR, UV, UNaV, and UKV but had no effect on blood pressure and RBF in sham control and ischemia-reperfusion kidneys. NMDA antagonist D-2-amino-5-phosphonopentanoic acid (D-AP-5) treatment completely abolished NMDA-induced renal dysfunction. D-AP-5 treatment significantly ameliorated ischemia-reperfusion-induced glomerular and tubular dysfunction by restoring decreased GFR, UV, and [U.sub.Na]V levels. Ischemia-reperfusion upregulates renal NMDA NR1 receptor expression, leading to reduced glomerular and tubular function in the kidneys. The NMDA antagonist can ameliorate ischemia-reperfusion-induced renal dysfunction. ischemia-reperfusion; kidney; glutamate; renal function

Stimulation of capsaicin receptors results in an increase in afferent renal nerve activity (ARNA), but it is unclear how capsaicin contributes to sensory activation intrarenally. Here, we studied the relationships between capsaicin receptor activation, substance P (SP) release, and the sensory response in the rat renal pelvis. Immunoblots showed that one of the capsaicin receptors, transient receptor potential vanilloid type 1 channel (TRPV1), was found in various renal tissues and was especially abundant in the renal pelvis, where most sensory nerve fibers originate. Interestingly, immunolabeling showed colocalization of TRPV1, SP, and the panneuronal marker PGP9.5 in the renal pelvis. Electrophysiological recordings showed that SP and capsaicin activated the same mechanosensitive ARNA in a single-unit preparation. Intrapelvic administration of capsaicin or a specific TRPV1 agonist, resiniferatoxin, resulted in a dose-dependent increase in multi-unit ARNA and SP release, and these effects were blocked by the TRVP1 blocker capsazepine. Inhibition of the SP receptor by L-703,606 largely prevented capsaicin- or resiniferatoxin-induced ARNA. Capsazepine also prevented intrapelvic pressure (IPP)-dependent ARNA activation and contralateral diuresis/natriuresis in the renorenal reflex at an IPP of 20 mmHg, but had no effect at an IPP of 50 mmHg. These data indicate that TRPV1, a low-pressure baroreceptor, is present in the renal pelvis and exclusively regulates neuropeptide release from primary renal afferent C-fibers in response to mechanostimulation. neurokinin-1 receptor; renorenal reflex; capsaicin receptor; intrapelvic pressure

Temporal decrease in renal sensory responses in rats after chronic ligation of the bile duct. Am J Physiol Renal Physiol 283: F164-F172, 2002. First published February 19, 2002; 10.1152/ajprenal.00231.2001.--Renal responses to renal sensory receptor activation were examined in rats after 1 and 4 wk of common bile duct ligation (CBDL). Compared with sham-operated rats (Sham), urine and sodium excretion after acute saline loading was significantly reduced at both times after CBDL. The blunted excretory responses in CBDL rats, accompanied by less activation of afferent renal nerve activity (ARNA), were already apparent at 1 wk and became severe at 4 wk. The defect in ARNA activation in CBDL rats was further studied using specific stimuli to activate renal sensory receptors. Graded increases in intrapelvic pressure or renal pelvic perfusion of substance P (SP) elicited an increase in ARNA in Sham rats, these responses being temporally attenuated in CBDL rats. Despite no significant change in renal pelvic SP release, no renorenal reflex was demonstrable in 4-wk CBDL rats. Immunoblotting showed that expression of renal pelvic neurokinin 1 (NK-1) receptors was 32 and 47% lower in 1- and 4-wk CBDL rats, respectively, than in Sham rats, this decrease correlating well with plasma SP levels. The quantitative real-time RT-PCR showed similar levels of NK-1 receptor mRNA in the renal pelvis in the Sham and 4-wk CBDL groups. We conclude that impairment of renal excretory and sensory responses increases with the duration of cirrhosis. An impaired renorenal reflex in cirrhotic rats is involved in the defective activation of the renal sensory receptors could be due, in part, to the low expression of NK-1 receptors, which is dependent on the duration of CBDL. The decrease in NK-1 receptor protein levels is not due to a decrease in mRNA levels. afferent renal nerve activity; renorenal reflex; substance P; neurokinin 1 receptor; cirrhosis

We previously demonstrated that the pulmonary vascular response to substance P (SP) increased in chronically hypoxic rats. This study explored the temporal increase in reactivity of the pulmonary vascular response to SP and its underlying mechanisms. First, young female Wistar rats were exposed to sea level (SL) or simulated high altitude (HA) for 15 h/day for 3 days, 1 wk, 2 wk, and 4 wk. Lungs were isolated and perfused with 4% bovine serum albumin in Krebs-Henseleit buffer solution. SP (1.5 x [10.sup.-4] M) induced significant increases in pulmonary arterial pressure ([P.sub.pa]), venous pressure ([P.sub.v]), capillary pressure ([P.sub.c]), arterial resistance ([R.sub.a]), and filtration coefficient ([K.sub.fc]) in SL lungs. Increases in [P.sub.pa] and [R.sub.a] were significantly augmented in HA lungs, with a temporal increase trend peaking at 2 wk of HA exposure. The selective neurokinin (NK) type 1 (N[K.sub.1]) receptor antagonist SR-14033 significantly attenuated SP-induced increases in [P.sub.pa], [P.sub.v], [P.sub.c], [R.sub.a], and [K.sub.fc] in SL lungs. In lungs exposed to HA for 2 wk, SR-14033 suppressed the effect of SP on [P.sub.pa]. Also, chronic hypoxia induced significant increases in N[K.sub.1] receptors and N[K.sub.1] receptor mRNA, with a temporal trend. We conclude that chronic hypoxia temporally augments SP-induced vascular responses, which are closely associated with increases in N[K.sub.1] receptors and gene expression. pulmonary hypertension; tachykinins; gene expression

A higher expression level of mitogenic fibroblast growth factor‐2 (FGF‐2) has been reported in human nasal mucus of both chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). Meanwhile, we have shown that long pentraxin 3 (PTX3), an essential component of humoral innate immunity that is produced at sites of infection and inflammation, was overproduced in human nasal mucosae and secretions of CRSsNP. Therefore, this study was aimed to investigate how FGF‐2 regulates PTX3 expression in human CRSsNP nasal mucosa‐derived fibroblast cells (hNMDFs). The FGF‐2 treatment caused ptx3 mRNA expression and PTX3 protein induction and secretion. In parallel, a differential expression of FGF receptor (FGFR)−1 to FGFR‐4 was observed in hNMDFs and human nasal tissues. While conventionally known PI3K/Akt/mTOR and AP‐1 pathways following FGFR activation were shown to be involved, the protein kinase Cδ (PKCδ) and cAMP response element‐binding protein (CREB) were also found to be as critical signaling molecules in FGF‐2‐induced PTX3 induction. The PKCδ and CREB activation could be detected in total cells and in the cell nucleus. Accordingly, a novel CREB binding sequence was detected in the human ptx3 promoter region and could interact with activated CREB in cells challenged with FGF‐2. Surprisingly, the phospholipase D (PLD), but not phosphoinositide‐ and phosphatidylcholine‐phospholipase C, was necessarily required for PKCδ and CREB activation. Therefore, we demonstrated here for the first time that FGF‐2 mediates PTX3 production not only through PI‐3K/Akt/mTOR and AP‐1 activation, but also through a novel FGFR–PLD–PKCδ–CREB cellular signaling pathway. [ABSTRACT FROM AUTHOR]