T-type calcium channel blockade as a therapeutic strategy against renal injury in rats with subtotal nephrectomy.

T-type calcium channel blockers have been previously shown to protect glomeruli from hypertension by regulating renal arteriolar tone. To examine whether blockade of these channels has a role in protection against tubulointerstitial damage, we used a stereo-selective T-type calcium channel blocker R(-)-efonidipine and studied its effect on the progression of this type of renal injury in spontaneously hypertensive rats that had undergone subtotal nephrectomy. Treatment with racemic efonidipine for 7 weeks significantly reduced systolic blood pressure and proteinuria. The R(-)-enantiomer, however, had no effect on blood pressure but significantly reduced proteinuria compared to vehicle-treated rats. Both agents blunted the increase in tubulointerstitial fibrosis, renal expression of alpha-smooth muscle actin and vimentin along with transforming growth factor-beta (TGF-beta)-induced renal Rho-kinase activity seen in the control group. Subtotal nephrectomy enhanced renal T-type calcium channel alpha1G subunit expression mimicked in angiotensin II-stimulated mesangial cells or TGF-beta-stimulated proximal tubular cells. Our study shows that T-type calcium channel blockade has renal protective actions that depend not only on hemodynamic effects but also pertain to Rho-kinase activity, tubulointerstitial fibrosis, and epithelial-mesenchymal transitions.

Expert recommendations on the challenges of hypertension in Asia.

A consensus meeting of leading Asian hypertension experts was held in January 2007 in Seoul, Korea, to discuss how to address the growing challenge of hypertension management in the region. This report summarises key recommendations from the group, including: raising public awareness about the impact of hypertension; improving physician education and training; increasing early detection, for example through routine blood pressure measurement; and development and adoption of pan-Asian treatment guidelines, which would greatly facilitate research into hypertension and its management. The group conclude that these challenges can only be met through a collaborative effort of government, healthcare professionals, food and healthcare industries, and patients and the public. Food and healthcare industries need to develop healthy foods and support healthy living programmes, while increasing research into antihypertensive medications in Asia. Government officials and policy makers need to be made aware of the value of investing in hypertension awareness, prevention and management programmes.

Adrenocortical steroidogenesis: studies on the mechanism of action of angiotensin and electrolytes.

The effects of adrenocorticotropin (ACTH), angiotensins I and II, increased potassium, and decreased sodium concentrations upon steroid synthesis were examined by incubation of beef adrenal tissue slices. Angiotensin II shared with ACTH the need for calcium and an inhibition of its effect in the presence of puromycin but differed in not stimulating cyclic adenosine monophosphate (AMP). Angiotensin I was effective in steroidogenesis. The stimulation of aldosterone synthesis by increased potassium concentration was accompanied by an increased level of cyclic AMP and was inhibited in the presence of puromycin. Decreased sodium concentration stimulated aldosterone synthesis but, alone of these stimuli, simultaneously decreased corticosterone levels. It therefore appears that ACTH and potassium stimulate steroidogenesis at an early step in the biosynthetic pathway through the activation of cyclic AMP, whereas the effect of angiotensins I and II involve another mechanism and decreased sodium concentration affects a later step in steroidogenesis.

Adrenocortical steroidogenesis: the effects of prostaglandins.

Prostaglandins E(1) and E(2) significantly stimulated the synthesis of aldosterone, corticosterone, and to a lesser degree, cortisol in the outer slices of beef adrenal tissue. PGA, PGF(1a), and PGF(2a) were ineffective.PGE(1) was found to stimulate steroidogenesis in a manner similar to that of adrenocorticotropin (ACTH) in (a) needing calcium, (b) being inhibited by puromycin but not actinomycin D, (c) increasing the levels of cyclic AMP, and (d) not having an additive effect to exogenous cyclic AMP. PGE(1) did not produce an additive effect with either submaximal or maximal amounts of ACTH but did have an additive effect with angiotensin. These results are in keeping with the hypothesis that PGE(1) shares a receptor site on the plasma membrane with ACTH.

Effect of isoproterenol on intracellular pH of the intercalated cells in the rabbit cortical collecting ducts.

To examine the mechanisms which regulate the functions of the intercalated cells (ICs) in the cortical collecting duct (CCD), the effect of isoproterenol on intracellular pH (pHi) of ICs was studied with the in vitro microperfused rabbit CCD, using the single cell pHi determination technique with fluorescent dye, 2',7'-bis-(2-carboxyethyl)-5(and-6)carboxyfluorescein. The pHi of beta-IC was significantly decreased with the addition of basolateral 10(-6) M isoproterenol (7.21 +/- 0.04 to 7.05 +/- 0.04), whereas alpha-IC did not show any change. This response of beta-IC to isoproterenol was dose-dependent and completely inhibited by the beta-blockers, atenolol or propranolol. The addition of forskolin or 8-Br-cAMP mimicked the effects of isoproterenol, suggesting that the activation of adenylate cyclase induced the decrease in pHi. The rate of pHi changes after the Cl- removal from the perfusate, which is considered to reflect the activity of luminal anion exchanger, was significantly higher with isoproterenol (0.032 +/- 0.009 pH unit/s) than that in the control (0.023 +/- 0.009 pH unit/s). The present studies provide direct evidence for the regulation of beta-IC function by beta-adrenergic receptor; and the luminal Cl-/HCO3- exchanger was considered to be stimulated by beta-agonist, directly.

Expression and distribution of aquaporin of collecting duct are regulated by vasopressin V2 receptor in rat kidney.

To examine whether expression and distribution of aquaporin of collecting duct (AQP-CD) are regulated by vasopressin V2 receptor (V2R), we performed immunohistochemical studies with specific antibody against AQP-CD. Normal Wistar rats were divided into four groups and treated for 3 d; control, dehydration, vasopressin V1 receptor (V1R) antagonist (OPC-21268 120 mg/kg), V2R antagonist (OPC-31260 30 mg/kg). At time of death, urine osmolality (Uosm) in the dehydration group (1884 +/- 245 mOsm/kg) was significantly higher than that in the control (938 +/- 91). In the V2R antagonist group, Uosm was significantly decreased to 249 +/- 29, whereas V1R antagonist showed no effect on Uosm. In the control and V1R antagonist groups, immunofluorescence studies showed the AQP-CD staining of both apical membrane and subapical cytoplasm of CD cells of the cortex and the inner medulla. Dehydration increased the immunostaining of both apical membrane and subapical cytoplasm of CD cells of the inner medulla, and the degree of increase was dominant in apical membrane. In the V2R antagonist group, only faint staining of apical membrane and weak labeling of cytoplasm of CD cells of the inner medulla were observed. These changes in the localization and protein amount of AQP-CD by dehydration and V2R antagonist were quantitatively confirmed by immunogold studies and immunoblot analysis of the inner medulla. The present results indicate that the distribution and amount of AQP-CD in the CD cells are regulated by vasopressin V2 receptor.

Pressure promotes DNA synthesis in rat cultured vascular smooth muscle cells.

High blood pressure is one of the major risk factors for atherosclerosis. In this study, we examined the effects of pressure on cell proliferation and DNA synthesis in cultured rat vascular smooth muscle cells. Pressure without shear stress and stretch promotes cell proliferation and DNA synthesis in a pressure-dependent manner. Pressure-induced DNA synthesis was inhibited significantly by the phospholipase C (PLC) inhibitor 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate, the protein kinase C inhibitor H-7, 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine, staurosporine, and the tyrosine kinase inhibitor ([3,4,5-trihydroxyphenyl]methylene)propanedinitrile. To clarify whether activation of PLC and calcium mobilization are involved in pressure-induced DNA synthesis, production of 1,4,5-inositol trisphosphate (IP3) and intracellular Ca2+ was measured. Pure pressure increased IP3 and intracellular Ca2+ in a pressure-dependent manner. The increases in both IP3 and intracellular Ca2+ were inhibited significantly by 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate. This study demonstrates a novel cellular mechanism whereby pressure regulates DNA synthesis in vascular smooth muscle cells, possibly via activation of PLC and protein kinase C.

Cellular mechanisms mediating rat renal microvascular constriction by angiotensin II.

To assess cellular mechanisms mediating afferent (AA) and efferent arteriolar (EA) constriction by angiotensin II (AngII), experiments were performed using isolated perfused hydronephrotic kidneys. In the first series of studies, AngII (0.3 nM) constricted AAs and EAs by 29+/-3 (n = 8, P < 0.01) and 27+/-3% (n = 8, P < 0.01), respectively. Subsequent addition of nifedipine restored AA but not EA diameter. Manganese (8 mM) reversed EA constriction by 65+/-9% (P < 0.01). In the second group, the addition of N-ethylmaleimide (10 microM), a Gi/Go protein antagonist, abolished AngII- induced EA (n = 6) but not AA constriction (n = 6). In the third series of experiments, treatment with 2-nitro-4-carboxyphenyl-N, N-diphenyl-carbamate (200 microM), a phospholipase C inhibitor, blocked both AA and EA constriction by AngII (n = 6 for each). In the fourth group, thapsigargin (1 microM) prevented AngII-induced AA constriction (n = 8) and attenuated EA constriction (8+/-2% decrease in EA diameter at 0.3 nM AngII, n = 8, P < 0.05). Subsequent addition of manganese (8 mM) reversed EA constriction. Our data provide evidence that in AAs, AngII stimulates phospholipase C with subsequent calcium mobilization that is required to activate voltage-dependent calcium channels. Our results suggest that AngII constricts EAs by activating phospholipase C via the Gi protein family, thereby eliciting both calcium mobilization and calcium entry.

Awareness of the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2000) and compliance to its recommendations: surveys in 2000 and 2004.

Clinic physicians' awareness of the Japanese hypertension guideline (JSH 2000) and compliance with its recommendations were assessed to derive policy implications for effective blood pressure control. Data were obtained from two postal questionnaire surveys conducted in 2000 and 2004, and subjects were 896 and 1425 clinic physicians, respectively, who were engaged in general internal medicine. Recognition rates of JSH 2000 were 63.1% (n = 822) before its announcement in 2000 and 94.4% (n = 1400) in 2004. Rates of access, familiarity and utilisation of JSH 2000 were 87.0, 81.6 and 68.9%, respectively (n = 1400) in 2004. As for major management strategies for low-risk hypertension: in 2000, for patients with 140-149/90-94 mmHg, 81.5% of 812 respondents performed lifestyle modification, and 11.2% prescribed medicines, whereas for patients with 150-159/95-99 mmHg, 71.7% of 807 respondents prescribed medicines, and 24.3% conducted lifestyle modification; in 2004, 90.0% of 1384 respondents conducted lifestyle modification, 22.6% prescribed medicines, 2.5% referred patients to other facilities, and 6.4% did nothing. In 2004, 68.9% of 1388 respondents agreed with the new definition of hypertension, whereas 17.1% preferred 160/95 mmHg. Respondents' age (P<0.05) and a percentage of hypertensives in daily patient load (P<0.0005) significantly associated with the choice of the old criteria. In conclusion, JSH 2000 achieved a substantial improvement in clinic physicians' awareness and their compliance to its recommendations on low-risk hypertension management. One of the strategies for further enhancement in their compliance with JSH 2004 would be its dissemination to those who are old and/or do not see hypertensive patients so frequently.

Characterization of subclones of Madin-Darby canine kidney renal epithelial cell line.

Heterogeneity in Madin-Darby canine kidney (MDCK) epithelial cells has been reported, however, its details have not been well described. In the present study, we show that subclones obtained from a MDCK cell line could be divided into two morphologically and biochemically distinct cell types with different hormonal responsiveness. Clones of the first type, motile clones, which had extended and flattened cytoplasm, were devoid of carbonic anhydrase activity. Clones of the second type, nonmotile clones, formed colonies of cuboidal cells and showed carbonic anhydrase activity. Motile clones synthesized cAMP in response to arginine vasopressin, prostaglandin E1, and isoproterenol but not glucagon. In contrast, nonmotile clones responded to all of these hormones. These findings suggest MDCK cells have multiple cellular origins. The motile clones have characteristics similar to the principal cells of the collecting system, whereas the nonmotile clones may be derived from the thick ascending limb or the intercalated cell. Our studies also demonstrate a significant influence of culture condition on MDCK cellular behavior (carbonic anhydrase activity, Na+/K+-ATPase activity and vasopressin responsiveness). Therefore, physiologic and biochemical experiments with MDCK cells must be interpreted with reservations about cellular heterogeneity as well as differences induced by culture conditions.

Conditional expression of anti-apoptotic protein p35 by Cre-mediated DNA recombination in cardiomyocytes from loxP-p35-transgenic mice.

p35, a viral inhibitor of caspase, prevents cell death induced by various stimuli. We established an experimental system to study the involvement of caspases in cell death, using primary cultured cells from p35 transgenic mice in which the p35 open reading frame (ORF) had been disrupted by the insertion of a DNA segment flanked by loxP sites, the Cre recognition sites. In this system, p35 expression can be initiated by Cre recombinase. Cardiomyocytes, which are highly sensitive to hypoxic stress, were infected with an adenovirus carrying the cre gene (AxCANCre). Expression of p35 by infection with AxCANCre resulted in inhibition of caspase-3 activation and resistance to hypoxia-induced cell death. Hypoxia-induced cytochrome c release was also attenuated in p35-expressing cardiomyocytes. Our transgenic mice can be used as an experimental model for studying the involvement of caspases in various degenerative diseases as well as programmed cell death both in vitro and in vivo.

Immune response to heat-shock protein correlates with induction of insulitis in I-E alpha d transgenic NOD mice.

To evaluate the correlation between heat-shock protein (HSP) and insulitis, we compared lymphocyte proliferative response to Mycobacterium leprae HSP65 of NOD mice with that of I-E alpha d transgenic NOD (I-E+NOD) mice, which show no insulitis. We found that splenocytes from 15-week-old NOD mice showed a more marked proliferative response to HSP than did those from age-matched I-E+NOD mice (P < 0.05). We then transferred splenocytes from 12-week-old NOD mice into I-E+NOD mice to induce insulitis in the recipients and examined antibody levels against HSP. By 6 weeks posttransfer, insulitis was successfully transferred to four out of five recipients of NOD splenocytes and antibody levels against HSP were significantly higher in the NOD splenocyte-transferred group than in controls, which showed no insulitis (P < 0.01). These results suggest that immune response to HSP correlates with insulitis in NOD mice. Our results support the assertion that HSP is a useful antigen for investigating the etiology of IDDM.

Selective genotyping with epistasis can be utilized for a major quantitative trait locus mapping in hypertension in rats.

Epistasis used to be considered an obstacle in mapping quantitative trait loci (QTL) despite its significance. Numerous epistases have proved to be involved in quantitative genetics. We established a backcross model that demonstrates a major QTL for hypertension (Ht). Seventy-eight backcrossed rats (BC), derived from spontaneously hypertensive rats (SHR) and normotensive Fischer 344 rats, showed bimodal distribution of systolic blood pressure (BP) values and a phenotypic segregation ratio consistent with 1:1. In this backcross analysis, sarco(endo)plasmic reticulum Ca(2+)-dependent ATPase (Serca) II heterozygotes showed widespread bimodality in frequency distribution of BP values and obviously demonstrated Ht. First, in genome-wide screening, Mapmaker/QTL analysis mapped Ht at a locus between D1Mgh8 and D1Mit4 near Sa in all 78 BC. The peak logarithm of the odds (LOD) score reached 5.3. Second, Serca II heterozygous and homozygous BC were analyzed separately using Mapmaker/QTL. In the 35 Serca II heterozygous BC, the peak LOD score was 3.8 at the same locus whereas it did not reach statistical significance in the 43 Serca II homozygotes. Third, to map Ht efficiently, we selected 18 Serca II heterozygous BC with 9 highest and 9 lowest BP values. In these 18 BC, the peak LOD score reached 8.1. In 17 of the 18, D1Mgh8 genotypes (homo or hetero) qualitatively cosegregated with BP phenotypes (high or low) (P < 0.0001, by chi-square analysis). In conclusion, selective genotyping with epistasis can be utilized for a major QTL mapping near Sa on chromosome 1 in SHR.

Long-term effects of statins on arterial pressure and stiffness of hypertensives.

Although lowering blood pressure (BP) reduces aortic stiffness, achieving the recommended BP goal can be difficult. Recent studies have shown that short-term use of statins can reduce BP significantly. To determine the long-term effects of statins on BP and aortic stiffness, a single-blind randomized prospective study was performed on 85 hyperlipidaemic hypertensive patients whose BP was insufficiently controlled by antihypertensive therapy. Every 3 months, aortic stiffness was assessed by measuring pulse wave velocity (PWV). Patients were randomly allocated to groups treated with pravastatin, simvastatin, fluvastatin, or a nonstatin antihyperlipidaemic drug. No significant differences in patient characteristics, kinds of antihypertensive drugs, BP, ankle brachial index, PWV, or serum lipid, creatinine, or C-reactive protein levels were found between the four groups at the start of the study. During the 12-month treatment period, PWV did not change in the pravastatin group or nonstatin group, but it was transiently reduced in the simvastatin group and significantly decreased in the fluvastatin group, even though the doses of the statins used in this study were lower than the usually prescribed dose. All four antihyperlipidaemic drugs significantly decreased serum cholesterol levels without affecting BP, ankle brachial index, or serum triglyceride levels. The C-reactive protein serum levels decreased significantly in the three statin groups but not in the nonstatin group. These results suggest that long-term use of fluvastatin by hyperlipidaemic hypertensive patients is associated with a significant reduction in aortic stiffness without any effect on BP.

Captopril therapy following percutaneous transluminal angioplasty for bilateral renal artery stenosis.

To establish an optimal approach for the patients with bilateral atherosclerotic renal artery stenosis, combined treatment involving percutaneous transluminal renal angioplasty and oral captopril was applied. Five patients were examined for effects of the combined treatment on blood pressure and renal function. After percutaneous transluminal renal angioplasty on one renal artery, the blood pressure (mean +/- SD) fell from 210/118 +/- 26/8 to 176/104 +/- 11/9 mm Hg without any deterioration of renal function. This reduced blood pressure was further lowered to 155/92 +/- 6/3 mm Hg by adding captopril therapy. This level of blood pressure has been maintained for an average of 37 months. Significant increases in serum creatinine concentration were not observed (124 +/- 27 vs 141 +/- 44 mumol/L), and renal size has been sustained. These results indicate that combined treatment with percutaneous transluminal renal angioplasty and captopril is effective in reducing the blood pressure and preserving renal function as an approach for the patients with bilateral atherosclerotic renal artery stenosis.

Elevated serum IP-10 levels observed in type 1 diabetes.

OBJECTIVE: Although most patients with type 1 diabetes are considered to have T-cell-mediated autoimmune disease, a method of measuring of pancreatic beta-cell-specific T-cell function in cases of type 1 diabetes has yet to be established. Here, we focused on interferon-inducible protein-10 (IP-10), a chemokine that promotes the migration of activated T-helper 1 (Th1) cells and measured serum IP-10 levels in patients with human type 1 diabetes, which is regarded as a Th1-mediated disease. RESEARCH DESIGN AND METHODS: Serum samples were obtained from diabetic patients, and the levels of autoantibodies (GAD and insulinoma-associated protein-2 [IA-2]) and IP-10 were measured. Diabetic patients positive for either or both of the autoantibodies were classified as Ab+ type 1, and those negative for both were classified as Ab type 1. To evaluate islet antigen-specific responses, peripheral blood from patients stimulated with or without GAD was used, and intracellular cytokine staining for flowcytometry was performed. RESULTS: The Ab+ and Ab- type 1 groups both showed a significantly higher serum IP-10 level than the healthy subjects (P < 0.001 and P < 0.05, respectively), and the IP-10 level in the recent-onset Ab+ subgroup was significantly higher than that in the established (longstanding) Ab+ subgroup (P < 0.002). Furthermore, there was a significant positive correlation between the serum IP-10 level and the number of GAD-reactive gamma-interferon-producing CD4+ cells in the Ab+ type 1 group (P < 0.007). CONCLUSIONS: Our findings demonstrate that measurement of serum IP-10 concentrations is useful in patients with type 1 diabetes.

NeuroD/beta2 gene G-->A polymorphism may affect onset pattern of type 1 diabetes in Japanese.

OBJECTIVE: The majority of type 1 diabetes is considered to be autoimmune with, for the most part, abrupt development. However, type 1 diabetes with slow onset, or the so-called slowly progressive type 1 diabetes or latent autoimmune diabetes in adults, has been recently recognized and is considered to be autoimmune-related. Although some investigators tried to explain the difference in onset pattern by the genetic background, including HLA type, it has not been established thus far. We hypothesized that the difference in onset pattern may relate to regeneration or differentiation of pancreatic beta-cells, and we therefore focused on the NeuroD/BETA2 gene, which encodes a transcription factor for the insulin gene and beta-cell differentiation. RESEARCH DESIGN AND METHODS: We examined the NeuroD/BETA2 gene polymorphism in 105 Japanese type 1 diabetic patients and in 122 nondiabetic Japanese subjects in a case-control study, and we stratified the patients according to their onset pattern and islet-associated autoantibody positivity. RESULTS: Regardless of the existence of islet-associated autoantibody, we found a significant difference in A allele frequency between type 1 diabetic patients with acute-onset type and control subjects. However, no difference was found between type 1 slow-onset diabetic patients and control subjects. CONCLUSIONS: These results support our hypothesis that NeuroD/BETA2 may affect the ability of regeneration of beta-cells, leading to a difference in the onset pattern and clinical course of type 1 diabetes.

Effects of furosemide and chlorothiazide on blood pressure and plasma renin activity.

Short (2 weeks) and long (12 weeks) term effects of furosemide and chlorothiazide on blood pressure, plasma renin activity, and uric acid concentration were studied in 69 hypertensive patients. Both treatments caused significant reductions in blood pressure and increases in plasma renin activity and uric acid at 2 and 12 weeks in 6) normal renin patients; there was no difference between the effects of furosemide and that of chlorothiazide. Reduction in blood pressure in eight low renin patients who showed smaller changes in plasma renin activity and uric acid was not significant at 2 weeks but significant after 12 weeks of treatment.

Aldosterone responses to angiotensin II, adrenocorticotropin, and potassium in chronic experimental diabetes mellitus in rats.

To investigate alterations in aldosterone secretion in diabetes mellitus, the effects of angiotensin II, ACTH, and potassium on aldosterone secretion were examined in conscious unrestrained streptozotocin-induced diabetic rats (60 mg/kg, 12 weeks before study). In chronic experimental diabetic rats where PRA, plasma aldosterone concentration, and urinary excretion of prostaglandin E2 were significantly decreased, a significant attenuated response of aldosterone secretion was demonstrated after infusion of angiotensin II, ACTH, or potassium. Yet the plasma fluorogenic corticosteroids response to ACTH in diabetic rats was not significantly different from that in control rats. After acute potassium infusion (0.30 meq/kg X min), plasma potassium levels in diabetic rats were significantly higher than in control rats, although immunoreactive insulin levels remained unchanged compared to the significant elevation in control rats. These results suggest that defects in aldosterone synthesis exist in chronic experimental diabetic rats and that potassium homeostasis is impaired during acute potassium loading. This change in potassium homeostasis may be related to both insulin and aldosterone deficiencies.

Dietary phosphorus deprivation induces 25-hydroxyvitamin D(3) 1alpha-hydroxylase gene expression.

Dietary phosphorus deprivation causes hypophosphatemia and an increase in serum 1alpha,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] concentrations. To determine the molecular mechanisms of this regulation, the effects of dietary phosphorus deprivation and hypophysectomy on 25-hydroxyvitamin D(3) 1alpha-hydroxylase (1alpha-hydroxylase) protein and messenger RNA (mRNA) expression were examined in rats. A low phosphorus diet (LPD) for 4 days resulted in hypophosphatemia and an increase in serum 1,25-(OH)(2)D(3) levels. This increase was caused by the induction of 1alpha-hydroxylase protein and mRNA expression (4- and 10-fold increases, respectively). Administration of the LPD or normal phosphorus diet to hypophysectomized (HPX) rats resulted in hypophosphatemia and suppression of 1alpha-hydroxylase gene expression, indicating that hypophosphatemia itself is not sufficient to induce 1alpha-hydroxylase mRNA expression. Administration of GH to HPX rats fed LPD could partially restore 1alpha-hydroxylase mRNA expression, whereas supplementation with insulin-like growth factor I, T(3), estrogen, or corticosterone had no effect. We also examined Phex gene expression in the bone, because the clinical features of X-linked hypophosphatemia resemble those of HPX rats. Phex mRNA expression, however, was not altered in HPX rats. In conclusion, we demonstrated that the increase in serum 1,25-(OH)(2)D(3) levels caused by dietary phosphorus deprivation is due to the induction of 1alpha-hydroxylase mRNA expression, and this increase is mediated in part by a GH-dependent mechanism.