Biomedical subjects

Hiroshi Nonoguchi

Publications and source records attributed to Hiroshi Nonoguchi.

30 records · Page 2Linked to original sources

PubMed2003

Inhibition of prostasin secretion by serine protease inhibitors in the kidney.

A serine protease, prostasin, has been shown to stimulate the activity of amiloride-sensitive sodium channels (ENaC). Prostasin is a glycosylphosphatidylinositol-anchored protein that is found free in physiologic fluids and tissue culture medium, but the mechanism by which prostasin is secreted from the cells has not been elucidated. The current studies found that serine protease inhibitor aprotinin blocked the secretion of prostasin in a mouse cortical collecting duct (CCD) cell line (M-1 cells). A synthetic serine protease inhibitor, nafamostat mesilate (NM), which is commonly used for the treatment of pancreatitis and disseminated intravascular coagulation in Japan, also inhibited the secretion of prostasin in M-1 cells. Continuous infusion of NM into rats resulted in a substantial decrease in urinary prostasin and urinary sodium excretion. p-guanidinobenzoic acid and 6-amidino-2-naphtol, catalytically inactive metabolites of NM, had no effect on prostasin secretion both in M-1 cells and in rats. These findings suggest that a serine protease-sensitive mechanism is involved in the secretion of prostasin in vitro as well as in vivo. Potassium secretion in the CCD is tightly linked to sodium reabsorption through EnaC; therefore, NM-induced decrease in prostasin secretion and subsequent inhibition of ENaC activity could account for the side effects of hyponatremia and/or hyperkalemia that are found sometimes in patients treated with NM. The results indicate an important role for prostasin in sodium reabsorption in the kidney under pathophysiologic conditions.

Animals↗

PubMed2003

Mechanisms of down-regulation of the renal parathyroid hormone receptor in rats with chronic renal failure.

Hypocalcemia, hyperphosphatemia and resistance to the action of parathyroid hormone (PTH) are well-characterized features in advanced chronic renal failure (CRF). Their pathogenesis has been attributed to both PTH receptor (PTH-R) down-regulation and postreceptor abnormalities. In this study, we examined the renal expression of the PTH-R mRNA in CRF (5/6 nephrectomy) rats. Experiments were also performed to determine whether an acidic condition and PTH itself influence PTH-R mRNA expression. RT-competitive PCR was used to examine mRNA expression, and polyclonal antibody against PTH-R was used for Western blot. PTH-R mRNA expression was abundant in glomeruli, proximal convoluted and straight tubules (PCT, PST), small in medullary and cortical thick ascending limbs, and cortical collecting ducts and not detectable in outer and inner medullary collecting ducts. The expression was significantly decreased in PCT and PST in CRF rats. Decrease in PTH-R mRNA expression was observed 1 week after the induction of CRF. PTH-R protein was decreased at 2 (-23%) and 4 (-45%) weeks in renal cortex, but not in medulla in CRF rats. PTH-R mRNA expression in PST was decreased by low pH (7.1 or 6.7) incubation compared with that at pH 7.4. PTH(1-34) (10(-9) M) increased PTH-R mRNA expression in PST from control rats by 250%. The stimulatory effect of PTH on PTH-R mRNA expression was decreased by the incubation at low pH medium. In summary, renal PTH-R is down-regulated in CRF rats. The decrease in mRNA expression in PCT and PST causes the decrease in PTH-R protein. Metabolic acidosis may participate in the down-regulation of PTH-R in early stage of CRF. This abnormality could be important in the pathogenesis of secondary hyperparathyroidism of CRF.

Acidosis↗

PubMed2003

Regulation of endothelin-converting enzyme 1 in nephrotic syndrome in rats.

BACKGROUND: Nephrotic syndrome is characterized by severe proteinuria and sodium and water retention. Although endothelin (ET) 1 can cause natriuresis or antinatriuresis, the role played by ET-1 in proteinuria and in sodium retention due to nephrotic syndrome remains unclear. METHODS: We investigated the role played by the ET-1 system in sodium and water retention and in proteinuria in puromycin aminonucleoside induced nephrotic syndrome in rats using microdissected nephron segments, competitive polymerase chain reaction, and Western blot. RESULTS: The expression of prepro ET-1, ET-converting enzyme 1 (ECE-1), and ET A receptor mRNAs, but not ET B receptor mRNA, in the glomeruli was increased in rats with nephrotic syndrome. The cGMP generation in the glomeruli induced by atrial natriuretic peptide and ET-1 was decreased, whereas the ET-3-induced cGMP generation was increased in rats with nephrotic syndrome. ECE-1 mRNA expression was increased not only in the glomeruli, but also in the thick ascending limbs and collecting ducts. The protein expression of ECE-1 was increased in the membrane fraction of the cortex and in the outer and the inner medulla of nephrotic rats. Blockade of ET A and B receptors by bosentan did not inhibit the occurrence of nephrotic syndrome. However, the administration of bosentan increased the urinary sodium excretion. CONCLUSION: These data suggest that an activated ET-1-ET A receptor pathway in glomeruli and/or an increased ECE-1 mRNA expression in distal segments may participate in sodium and water retention, but not in the occurrence of nephrotic syndrome.

Animals↗

PubMed2003

Type 1A angiotensin II receptor is regulated differently in proximal and distal nephron segments.

Angiotensin II plays important roles in renal vasoconstriction, sodium reabsorption in proximal tubules, and cell proliferation. Angiotensin II receptors are present not only in proximal but also in distal tubules. We investigated the effects of dehydration on the mRNA expression of type 1A angiotensin II receptor (AT1A) in proximal and distal nephron segments and on the expression of type 1 angiotensin II receptor (AT1) protein. Competitive polymerase chain reaction was employed to quantitatively examine mRNA expression, and AT1-specific polyclonal antibody was used for Western blot analysis. AT1A mRNA expression was most abundant in glomeruli. Collecting ducts showed higher expressions than did proximal tubules or thick ascending limbs. Dehydration caused an increase of AT1A mRNA expression in glomeruli, proximal straight tubules (PST), and medullary and cortical thick ascending limbs (MAL and CAL, respectively). In contrast, dehydration decreased AT1A mRNA expression in cortical, outer medullary, and inner medullary collecting ducts (CCD, OMCD, and IMCD, respectively). Incubation of isolated glomeruli, PST, and IMCD in hypertonic solution made by NaCl and mannitol in vitro increased AT1A mRNA expression. Incubation of IMCD with AVP (10(-7) mol/l) also increased AT1A mRNA expression. AT1 was detected at 45 kDa by Western blotting. Dehydration caused a decrease and increase of AT1 expression in the cortex and the medulla, respectively. In summary, these data showed that the mechanisms of the regulation of AT1A differ between proximal and distal tubules. The finding that AT1 was up-regulated in the medulla during dehydration may suggest that this receptor plays an important role in dehydration in the distal tubules.

Animals↗

PubMed2003

Acute regulation of the epithelial sodium channel gene by vasopressin and hyperosmolality.

The amiloride-sensitive epithelial sodium channel (ENaC) plays a key role in sodium reabsorption in the collecting ducts. We examined ENaC mRNA distribution along the nephron and acute effects of vasopressin and hyperosmolality on ENaC mRNA expression. ENaCalpha, beta, and gamma mRNA expressions were observed in cortical, outer medullary and initial inner medullary collecting ducts (CCD, OMCD and ilMCD, respectively). ENaCalpha mRNA expression was also observed in medullary and cortical thick ascending limbs (MAL and CAL, respectively), while ENaCbeta and gamma mRNA expressions were not observed. Furthermore, ENaCalpha mRNA expression in MAL but not in collecting ducts was stimulated by acute exposure to arginine vasopressin (AVP), 8-(4-chlorophenylthio) (CPT)-cAMP and hyperosmolality. However, the physiological significance of these effects is not known, since ENaC protein is reported to be absent in MAL. These data suggest that ENaCalpha mRNA expression in MAL but not in collecting ducts is acutely regulated by AVP and hyperosmolality. The absence of stimulation of ENaCalpha mRNA expression in collecting ducts suggests the physiological significance of ENaCbeta and gamma mRNA for acute regulation by vasopressin. Determining the physiological significance of the acute effect of vasopressin in MAL will require further investigations.

Animals↗

PubMed2002

Regulation of prostasin by aldosterone in the kidney.

Prostasin is a serine protease present in mammalian urine that increases the activity of the epithelial sodium channel (ENaC) when the two are coexpressed in Xenopus oocytes. To determine if aldosterone, one of the principal regulators of urinary Na reabsorption by the distal nephron, affects prostasin expression, we examined prostasin mRNA and protein in a cultured mouse cortical collecting duct cell line (M-1), whole rats, and patients with primary aldosteronism. Aldosterone treatment of M-1 cells substantially increased prostasin expression and stimulated (22)Na uptake. Urinary excretion of prostasin in rats that were infused with aldosterone likewise increased by approximately 4-fold when compared with the vehicle-infused rats. Finally, urinary excretion of prostasin in patients with primary aldosteronism was substantially increased when compared with normal patients. Adrenalectomy reduced urinary prostasin excretion to control levels, whereas urinary prostasin levels were not altered in patients undergoing surgery for other reasons. In patients with primary aldosteronism, reduction in the urinary excretion of prostasin correlated with the increase in the urinary Na/K ratio. These findings, together with our previous report that prostasin activates the amiloride-sensitive Na currents through ENaC, demonstrate that prostasin regulates Na balance in vivo by virtue of its heightened expression in the presence of aldosterone.

Adrenalectomy↗

PubMed2002

Galpha13 induces preproET-1 gene expression via JNK.

The endothelin B receptor (ETBR) has been shown to mediate autoinduction of endothelin-1 (ET-1). We previously reported that the ET(B)R interacts with Galpha13, a member of the heterotrimeric GTP-binding protein family. In the present study, we examined whether Galpha13 induces preproET-1 (ppET-1) gene transcription, which could result in ET-1 autoinduction in a renal epithelial cell line. We generated a reporter gene construct under control of the ppET-1 promoter region. The construct was transiently expressed in COS-7 cells. Transient expression of ETBR increased the promoter activity of ppET-1 following treatment with 100 nmol/l of ET-1. Expression of Galpha13Q226L or Galpha9209L, constitutively active forms of Galpha13 and Galpha9, also activated the ppET-1 promoter. ETBR-stimulated ppET-1 promoter activity was partially diminished by the expression of dominant negative forms of c-Jun N-terminal kinase (JNK1APF) or MAPK/ERK kinase (MEKK97M). Expression of JNK1APF also inhibited Galpha13Q226L-induced ppET-1 promoter activation. These findings indicate that Galpha13 can induce ppET-1 gene expression through a JNK-mediated pathway. Our results also suggest that this Galpha13-coupled signaling pathway may play an important role in a sustained ET-1 autoinduction loop in various pathophysiological conditions.

Animals↗

PubMed2002

[Effects of fluvastatin on plasma lipid abnormalities in hemodialysis patients with chronic renal failure].

Fluvastatin, an HMG-CoA reductase inhibitor, was administered at a dosage of 20 mg/day for 24 weeks to 11 hemodialysis patients with a high plasma total cholesterol (TC) level (> or = 220 mg/dl). Serum lipids, apolipoprotein, and malondialdehyde (MDA) levels were measured every 12 weeks. After 24 weeks of fluvastatin administration, the TC level had decreased by 10.5% (238 +/- 15 mg/dl-->203 +/- 25 mg/dl), the low density lipoprotein cholesterol (LDL-C) level had decreased by 16.2% (142 +/- 32 mg/dl-->119 +/- 26 mg/dl), and the HDL-C level had increased by 23.4% (47 +/- 15 mg/dl-->58 +/- 19 mg/dl). These changes were statistically significant and resulted in a reduction of the atherogenic index (AI: TC-HDL-C/HDL-C). The triglyceride (TG) level did not change significantly. The apolipoprotein A1 level increased by 9.1% (121 +/- 22 mg/dl-->132 +/- 20 mg/dl) and the apolipoprotein B level decreased by 20.2% (114 +/- 25 mg/dl-->91 +/- 20 mg/dl). The MDA level also decreased significantly (1.16 +/- 0.92 nmol/ml-->0.58 +/- 0.38 nmol/ml). No particular side effects were observed during the 24 weeks of fluvastatin administration. In conclusion, fluvastatin may play an important role in preventing significant oxidative stress and was shown to be safe and effective in reducing the TC, LDL-C, MDA and AI levels in dialysis patients with hypercholesterolemia. The possibility that this improvement in the plasma lipid profile of dialysis patients may decrease atherogenic complications requires further investigation, including long-term clinical observations.

Aged↗

PubMed2002

[A case of secondary hyperparathyroidism with an ectopic intrathyroid gland successfully diagnosed and controlled by percutaneous ethanol injection therapy (PEIT)].

Secondary hyperparathyroidism (II HPT) is a major complication in chronic dialysis patients, and percutaneous ethanol injection therapy (PEIT) has become a useful alternative treatment for II HPT. However, the existence of ectopic parathyroid glands is a major problem when conducting PEIT. Ectopic parathyroid gland accepts 10-35% of II HPT, and the missing glands cannot be detected consistently by any imaging techniques, including scintigraphy. Intrathyroid parathyroid gland is as rare as about 1% and recurrence of missing glands after parathyroidectomy (PTx) has been reported in some cases. We report here a 52-year-old female in whom an ectopic parathyroid gland was defected successfully and intact-PTH controlled by tentative PEIT. At the first examination, a left parathyroid adenoma and a right thyroid goiter were pointed out by ultrasonography, CT and scintigraphy. PEIT was applied twice to the left parathyroid adenoma, but intact-PTH was not decreased. Ultrasonography, CT, 201Tl-99mTc subtraction scintigraphy and fine needle aspiration biopsy (FNAB) were performed again to search for the existence of ectopic glands. The results suggested that the right intrathyroid tumor was an ectopic parathyroid gland. Consequently, tentative PEIT was applied to the right intrathyroid tumor, and successful control of intact-PTH and serum Ca was eventually achieved. To our knowledge, this is the first reported case of secondary hyperparathyroidism with an ectopic intrathyroid gland that was successfully controlled by PEIT. In this case, it was suggested that tentative PEIT of intrathyroid tumor was a useful method for detecting an ectopic parathyroid gland.

Adenoma↗

PubMed2002

[Not Available].

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Journal Article↗

PubMed2001

Upregulation of the secretory-type Na(+)/K(+)/2Cl(-)-cotransporter in the kidney by metabolic acidosis and dehydration in rats.

The functional role and mechanisms of regulation of the Na(+)/K(+)/2Cl(-)-cotransporter NKCC1 in the kidney have not yet been clarified. NKCC1 mRNA and protein expression in control rats, rats with dehydration (2 d), and rats with metabolic acidosis (NH(4)Cl in the food for 6 to 7 d) was examined using reverse transcription-PCR and Western blotting. In contrast to the abundant NKCC1 mRNA expression in the terminal inner medullary collecting ducts in mice, expression was found to be most abundant in the outer medullary collecting ducts (OMCD) in rats. Dehydration and metabolic acidosis increased NKCC1 mRNA expression three- to fivefold not only in the OMCD but also in the cortical collecting ducts and inner medullary collecting ducts. Dehydration and metabolic acidosis increased NKCC1 protein expression twofold in the membrane fraction from the outer medulla. NKCC1 protein expression was observed not in the microdissected medullary thick ascending limbs but in the OMCD, and it was stimulated twofold by dehydration and metabolic acidosis. Incubation of OMCD in low-pH medium increased NKCC1 mRNA expression. In summary, NKCC1 mRNA and protein expression is upregulated with dehydration and metabolic acidosis. NKCC1 may play an important role in adaptation to these physiologic conditions. Low pH and possibly hypertonicity stimulate NKCC1 mRNA expression in OMCD.

Acidosis↗

PubMed2001

Activation of epithelial sodium channels by prostasin in Xenopus oocytes.

Prostasin, a novel serine protease, was purified from seminal fluid, and its cDNA sequence was determined. Expression of prostasin was detected in human tissues, including prostate, kidney, and lung, as well as bodily fluids, including seminal fluid and urine. However, its physiologic role in the human body is not known. Recently, a novel regulatory mechanism by which serine proteases activate epithelial sodium channel in the Xenopus oocyte was identified. Therefore, it was hypothesized that prostasin could activate sodium currents, and a rat prostasin cDNA clone was isolated to investigate its physiologic function. Rat prostasin mRNA is expressed predominantly in kidney, and lower levels of expression were detected in prostate, lung, colon, stomach, and skin. These all are epithelial tissues in which the epithelial sodium channel (ENaC) is expressed. Coexpression of rat prostasin and rat ENaC in Xenopus oocytes increased the amiloride-sensitive sodium current by twofold. Preincubation of oocytes that expressed prostasin with aprotinin did not result in an increase in sodium current, compared with the control. The removal of aprotinin from the bath solution resulted in a twofold increase of the current only in oocytes that expressed prostasin, which indicates that protease activity of prostasin is required for the ENaC activation. Expression of rat prostasin had no effect on the potassium current when expressed with rat renal outer medulla K channel, which shows specificity of prostasin action for ENAC: These results indicate that prostasin acts as an extracellular regulator of ENAC:

Amiloride↗