Vasopressin V1a receptor is required for nucleocytoplasmic transport of mineralocorticoid receptor.

We previously reported that a deficiency in the vasopressin V1a receptor (V1aR) results in type 4 renal tubular acidosis, which suggests that vasopressin exerts direct effects on the physiological actions of aldosterone. We investigated the role of vasopressin for nucleocytoplasmic transport of mineralocorticoid receptor (MR) in the intercalated cells. Vasopressin V1aR-deficient (V1aR(-/-)) mice showed largely decreased expression of MR and 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2) in the medulla of the kidney, which was partially ameliorated by fludrocortisone treatment. The incubation of IN-IC cells, an intercalated cell line established from temperature-sensitive SV40 large T antigen-expressing rats, with aldosterone or vasopressin increased the nuclear-to-cytoplasmic ratio of the MR from 11.2 to 47.2% and from 18.7 to 61.2%, respectively, in 30 min without any changes in MR expression from the whole cell extract. The immunohistochemistry analysis of the IN-IC cells revealed the nuclear accumulation of MRs after a 30-min incubation with aldosterone or vasopressin. These effects were accompanied by an increase in regulator of chromosome condensation-1 (RCC-1) due to aldosterone and a decrease in Ran GTPase-activating protein 1 (Ran Gap1) due to vasopressin. RNA interference against V1aR abolished the nuclear accumulation of MR induced by aldosterone or vasopressin. Vasopressin increased PKCα and -ß(1) expression, and aldosterone increased PKCδ and -ζ expression, but these effects were abolished with a V1aR knockdown. These results suggest that vasopressin directly regulates the nucleocytoplasmic transport of MRs via the V1aR in the intercalated cells of the collecting ducts.

Persistent homocysteine metabolism abnormality accelerates cardiovascular disease in hemodialyzed patients--the Nishinomiya Study.

OBJECTIVE: Homocysteine (Hcy) is an intermediate in sulfur amino acid metabolism and may induce oxidative stress. Several studies have reported that elevated Hcy in end-stage renal failure may contribute to cardiovascular disease (CVD). The purpose of this study is to investigate whether the changes in Hcy levels correlate better with the CVD outcomes than baseline Hcy level. METHODS: A total of 187 patients on dialysis participated in the present prospective observational study and were followed up for 107 months. Baseline cross-sectional analysis of the relationship between Hcy and several factors related to its metabolism was performed, along with survival analysis for the occurrence of CVD. All subjects were divided into the Increase or Decrease of Hcy group on the basis of changes in Hcy from baseline to year 3. RESULTS: The occurrence of CVD was higher in the Increase (30.1%) than in the Decrease group (9.0%). Greater change of Hcy was associated with risk of CVD (hazard ratio: 3.658) after adjusting basic factors and nutritional status. In stepwise multiple analyses, serum folate, vitamin B(12), cysteine, creatinine, and body mass index were considered to be independent predictors of Hcy. CONCLUSIONS: These data show that increase in Hcy is a powerful predictor of the occurrence of CVD in patients on dialysis.

Aldosterone requires vasopressin V1a receptors on intercalated cells to mediate acid-base homeostasis.

Both aldosterone and luminal vasopressin may contribute to the maintenance of acid-base homeostasis, but the functional relationship between these hormones is not well understood. The effects of luminal vasopressin likely result from its interaction with V1a receptors on the luminal membranes of intercalated cells in the collecting duct. Here, we found that mice lacking the V1a receptor exhibit type 4 renal tubular acidosis. The administration of the mineralocorticoid agonist fludrocortisone ameliorated the acidosis by restoring excretion of urinary ammonium via increased expression of Rhcg and H-K-ATPase and decreased expression of H-ATPase. In a cell line of intercalated cells established from transgenic rats expressing the mineralocorticoid and V1a receptors, but not V2 receptors, knockdown of the V1a receptor gene abrogated the effects of aldosterone on H-K-ATPase, Rhcg, and H-ATPase expression. These data suggest that defects in the vasopressin V1a receptor in intercalated cells can cause type 4 renal tubular acidosis and that the tubular effects of aldosterone depend on a functional V1a receptor in the intercalated cells.

Pathological role of aminolevulinate in uremic patients.

Previous reports have demonstrated that δ-aminolevulinate (ALA) can promote iron release from horse spleen ferritin under conditions of high serum ALA levels in uremia; therefore, we speculated that the accumulated ALA in uremic patients would stimulate iron release from ferritin, resulting in accelerated oxidative stress and uremic complications. We measured the plasma ALA of uremic patients and examined the ALA-induced iron release from human ferritin. The participants consisted of 30 hemodialysis patients and 14 healthy subjects. Plasma malondialdehyde was measured as a surrogate marker of lipid peroxidation. The plasma exchange effluent from two patients who had undergone plasma exchange (for the treatment of systemic lupus erythematosus and acute myeloblastic leukemia) was collected and treated to obtain the human ferritin-rich fraction. Iron release from ferritin was examined using bathophenanthroline sulfate. The influence of antioxidants and different pH levels on iron release were investigated. Plasma ALA and malondialdehyde concentration in the hemodialysis patient was significantly higher than that in healthy subjects. ALA was positively correlated with malondialdehyde. The abundance of iron release was dependent on the ALA concentration and incubation time. Iron release at the high pH of 7.6 was decreased compared with that at pH 7.4. Citrate increased iron release at pH 7.4, but citrate-stimulated iron release was totally abolished at pH 7.6. Our study suggests that ALA accumulation may have a role to play in certain complications in uremic patients, such as oxidative stress, by releasing iron from ferritin.

Switching from calcium carbonate to sevelamer hydrochloride has suppressive effects on the progression of aortic calcification in hemodialysis patients: assessment using plain chest X-ray films.

Sevelamer hydrochloride, a non-aluminum- and non-calcium-containing hydrogel, is an effective phosphate binder in dialysis patients. The suppressive effect of the switching from calcium carbonate to sevelamer hydrochloride on the progression of vascular calcification was examined by measuring areas of calcification on routine chest X-rays using image-analyzing software. The data of 69 maintenance hemodialysis patients were analyzed retrospectively. Over a period of 18 months, 19 patients took only sevelamer hydrochloride as a phosphate binder, while the other 50 patients took only calcium carbonate. The area of calcification increased in the calcium carbonate group, but did not change significantly in the sevelamer group. While the usefulness of computed tomography in detecting vascular calcification in hemodialysis patients has been reported previously, the suppressive effects of switching from calcium carbonate to sevelamer hydrochloride on the progression of aortic calcification can be observed without computed tomography by using the plain chest X-ray films that are routinely performed in hemodialysis clinics.