Biomedical subjects

Kenichiro Kitamura

Publications and source records attributed to Kenichiro Kitamura.

23 records · Page 2Linked to original sources

PubMed2002

Endothelin receptor antagonists prevent parathyroid cell proliferation caused by hypocalcemia in rats.

PURPOSE OF REVIEW: Secondary hyperparathyroidism in chronic renal failure is one of the most frequently encountered disorders of calcium homeostasis, characterized by parathyroid hypertrophy and hyperplasia. It is important to understand the pathogenesis of parathyroid epithelial cell hyperplasia and to determine the factors involved in the parathyroid cell proliferation for the development of the new therapeutic strategy for the secondary hyperparathyroidism. The existence of the endothelin system in the parathyroid gland and the involvement of the endothelin system in the proliferation of parathyroid cells have recently been demonstrated. The purpose of this review is to summarize the recent findings on the role of the endothelin system in the parathyroid cell proliferation, and to discuss the effect of the endothelin receptor antagonists for the treatment of the secondary hyperparathyroidism. RECENT FINDINGS: It was recently demonstrated that the inhibitory effect of endothelin receptor antagonist, bosentan, on the proliferation of parathyroid cells in secondary hyperparathyroidism rats induced by the low calcium diet. The treatment of the low calcium diet rats with bosentan was found to substantially reduce the number of PCNA-positive parathyroid cells, wet weight of parathyroid gland, and serum PTH level. SUMMARY: The effectiveness of the endothelin receptor antagonists for the prevention of the low calcium diet-induced secondary hyperparathyroidism in rats has been clearly demonstrated. These findings suggest the possibility that endothelin receptor antagonist might become one of the important therapeutic strategies for preventing secondary hyperparathyroidism in humans.

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↗

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↗

PubMedDate not supplied

Cloning and characterization of a transmembrane-type serine protease from rat kidney, a new sodium channel activator.

We have cloned the gene of a new transmembrane-type serine protease from rat kidney, which activates sodium channels. The amino acid sequence deduced from a full-length cDNA revealed that transmembrane serine protease-1 (TMSP-1) is a member of the clan SA/family S1 of serine proteases, comprising a 30 amino acid prepropeptide, a mature form sequence of 274 amino acids starting with the Ile-Val-Gly-Gly-Gln motif, and a common catalytic triad of serine proteases. The hydrophobic amino acid sequence in the carboxy-terminus of this enzyme suggests that it is a glycosylphosphatidylinositol-anchored protein. As revealed by quantitative reverse transcription-polymerase chain reaction analysis, it is highly expressed in kidney, small intestine, and stomach, and moderately expressed in lung, thymus, spleen and skin. The recombinant protease had an optimal pH at 9.0, selectively cleaved synthetic peptide substrates of trypsin, and was inhibited by aprotinin, leupeptin and benzamidine. Immunohistochemical studies revealed that this protease is predominantly expressed in cells from collecting ducts of the renal medulla. We also demonstrate that a C-terminally truncated variant of TMSP-1 significantly activates the epithelial sodium channel, and that its mRNA levels are upregulated by aldosterone. These observations suggest that it is a new member of the trypsin-type transmembrane proteases, which regulate sodium balance by activating the epithelial sodium channel.

Aldosterone↗