[Bone and calcium metabolism in life-style related diseases].

Accumulating evidence shows that life-style related diseases such as diabetes mellitus, hypertension, dyslipidemia are associated with bone and calcium metabolism. Patients with diabetes mellitus have increased fracture risks, independently of bone mineral density, with abnormality of parathyroid hormone secretion and impaired osteoblastic function. On the other hand, osteocalcin secreted from bone is reported to regulate glucose metabolism. Thus, bone, calcium and glucose metabolism may be deeply associated with each other. In this review, we describe the association between life-style related diseases, especially diabetes mellitus, and metabolism of bone and calcium.

PhenoMiner: a quantitative phenotype database for the laboratory rat, Rattus norvegicus. Application in hypertension and renal disease.

Rats have been used extensively as animal models to study physiological and pathological processes involved in human diseases. Numerous rat strains have been selectively bred for certain biological traits related to specific medical interests. Recently, the Rat Genome Database (http://rgd.mcw.edu) has initiated the PhenoMiner project to integrate quantitative phenotype data from the PhysGen Program for Genomic Applications and the National BioResource Project in Japan as well as manual annotations from biomedical literature. PhenoMiner, the search engine for these integrated phenotype data, facilitates mining of data sets across studies by searching the database with a combination of terms from four different ontologies/vocabularies (Rat Strain Ontology, Clinical Measurement Ontology, Measurement Method Ontology and Experimental Condition Ontology). In this study, salt-induced hypertension was used as a model to retrieve blood pressure records of Brown Norway, Fawn-Hooded Hypertensive (FHH) and Dahl salt-sensitive (SS) rat strains. The records from these three strains served as a basis for comparing records from consomic/congenic/mutant offspring derived from them. We examined the cardiovascular and renal phenotypes of consomics derived from FHH and SS, and of SS congenics and mutants. The availability of quantitative records across laboratories in one database, such as these provided by PhenoMiner, can empower researchers to make the best use of publicly available data. Database URL: http://rgd.mcw.edu.

Macrophage mineralocorticoid receptor signaling plays a key role in aldosterone-independent cardiac fibrosis.

Mineralocorticoid receptor (MR) activation promotes the development of cardiac fibrosis and heart failure. Clinical evidence demonstrates that MR antagonism is protective even when plasma aldosterone levels are not increased. We hypothesize that MR activation in macrophages drives the profibrotic phenotype in the heart even when aldosterone levels are not elevated. The aim of the present study was to establish the role of macrophage MR signaling in mediating cardiac tissue remodeling caused by nitric oxide (NO) deficiency, a mineralocorticoid-independent insult. Male wild-type (MRflox/flox) and macrophage MR-knockout (MRflox/flox/LysMCre/+; mac-MRKO) mice were uninephrectomized, maintained on 0.9% NaCl drinking solution, with either vehicle (control) or the nitric oxide synthase (NOS) inhibitor NG-nitro-l-arginine methyl ester (L-NAME; 150 mg/kg/d) for 8 wk. NO deficiency increased systolic blood pressure at 4 wk in wild-type L-NAME/salt-treated mice compared with all other groups. At 8 wk, systolic blood pressure was increased above control in both L-NAME/salt treated wild-type and mac-MRKO mice by approximately 28 mm Hg by L-NAME/salt. Recruitment of macrophages was increased 2- to 3-fold in both L-NAME/salt treated wild-type and mac-MRKO. Inducible NOS positive macrophage infiltration and TNFα mRNA expression was greater in wild-type L-NAME/salt-treated mice compared with mac-MRKO, demonstrating that loss of MR reduces M1 phenotype. mRNA levels for markers of vascular inflammation and oxidative stress (NADPH oxidase 2, p22phox, intercellular adhesion molecule-1, G protein-coupled chemokine receptor 5) were similar in treated wild-type and mac-MRKO mice compared with control groups. In contrast, L-NAME/salt treatment increased interstitial collagen deposition in wild-type by about 33% but not in mac-MRKO mice. mRNA levels for connective tissue growth factor and collagen III were also increased above control treatment in wild-type (1.931 ± 0.215 vs. 1 ± 0.073) but not mac-MRKO mice (1.403 ± 0.150 vs. 1.286 ± 0.255). These data demonstrate that macrophage MR are necessary for the translation of inflammation and oxidative stress into interstitial and perivascular fibrosis after NO deficiency, even when plasma aldosterone is not elevated.

The vascular smooth muscle cell in arterial pathology: a cell that can take on multiple roles.

Vascular smooth muscle cells (VSMCs) are the stromal cells of the vascular wall, continually exposed to mechanical signals and biochemical components generated in the blood compartment. They are involved in all the physiological functions and the pathological changes taking place in the vascular wall. Owing to their contractile tonus, VSMCs of resistance vessels participate in the regulation of blood pressure and also in hypertension. VSMCs of conduit arteries respond to hypertension-induced increases in wall stress by an increase in cell protein synthesis (hypertrophy) and extracellular matrix secretion. These responses are mediated by complex signalling pathways, mainly involving RhoA and extracellular signal-regulated kinase1/2. Serum response factor and miRNA expression represent main mechanisms controlling the pattern of gene expression. Ageing also induces VSMC phenotypic modulation that could have influence on cell senescence and loss of plasticity and reprogramming. In the early stages of human atheroma, VSMCs support the lipid overload. Endocytosis/phagocytosis of modified low-density lipoproteins, free cholesterol, microvesicles, and apoptotic cells by VSMCs plays a major role in the progression of atheroma. Migration and proliferation of VSMCs in the intima also participate in plaque progression. The medial VSMC is the organizer of the inwardly directed angiogenic response arising from the adventitia by overexpressing vascular endothelial growth factor in response to lipid-stimulated peroxisome proliferator-activated receptor-γ, and probably also the organizer of the adventitial immune response by secreting chemokines. VSMCs are also involved in the response to proteolytic injury via their ability to activate blood-borne proteases, to secrete antiproteases, and to clear protease/antiprotease complexes.

Elevated retinol binding protein 4 contributes to insulin resistance in spontaneously hypertensive rats.

Retinol binding protein 4 (RBP4) is an adipokine secreted by adipose tissue and liver and contributes to insulin resistance (IR) in animals. Although several human studies indicated that RBP4 is positively correlated with blood pressure and is elevated in untreated hypertensive subjects, the role of RBP4 in IR of hypertensive animals still remains obscure. In this study, spontaneously hypertensive rats (SHR) were used to investigate the relationship between RBP4 levels and IR. We found that at 7 weeks old, SHR had significantly increased plasma RBP4 levels and RBP4 expression in liver and epididymal adipose tissue accompanied by worsening of IR as compared with Wistar-Kyoto (WKY) control rats. Administration of fenretinide in SHR to increase urinary RBP4 excretion significantly decreased plasma RBP4 levels and improved IR. Moreover, treatment with valsartan markedly reduced blood pressure, circulating RBP4 and adiponectin levels, and IR in SHR. Valsartan also reversed the increase of hepatic gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and the decrease of type 4 glucose transporter (GLUT4) in adipose tissue. In conclusion, these results suggest that RBP4 contributes, at least partly, to the pathogenesis of IR in SHR. Furthermore, the decrease of blood pressure caused by valsartan not only decreased RBP4 levels, but also improved IR in SHR.

Nephrectomy modifies renal angiotensin II effects in kidney donors.

BACKGROUND: Age, gender, menopausal status, a family history of hypertension, and renal vascular response to angiotensin II are involved in the progression of renal failure from its very beginning. METHODS: In order to investigate their importance on this progression, we measured effective renal plasma flow (ERPF) and glomerular filtration rate (GFR), and calculated glomerular pressure (Pglo) and afferent and efferent arteriole resistances (by means of Gomez formulae) in 26 normotensive kidney donors before and after nephrectomy. RESULTS: Renal reactivity to angiotensin was the only variable that affected changes in renal and glomerular hemodynamics after the loss of renal tissue: in subjects with greater angiotensin reactivity, higher afferent resistances (Ra) and lower glomerular filtration and pressure before nephrectomy change to higher efferent resistances (Re) and higher Pglo and filtration after nephrectomy. CONCLUSIONS: In normotensive donors with a normal compensatory response to nephrectomy, baseline renal reactivity to angiotensin II can influence renal and glomerular hemodynamics 1 year after nephrectomy.

Cerebral oxygen supply during hypotension in near-term lambs: a near-infrared spectroscopy study.

Sufficient O(2)-supply to the brain is necessary for an adequate cerebral energy metabolism, function and growth. To elucidate the relation between changes in, respectively, mean arterial blood pressure (MABP) and cerebral O(2)-supply and changes in the oxygenation state of hemoglobin during hypotension in preterm born lambs. Preterm lambs were delivered at 141 days (n=7) or 127 days (n=7) of gestation. Hypotension was induced by stepwise withdrawal of blood. Cerebral arterial blood gases were analyzed at the end of each level to calculate cerebral O(2)-supply. Near-infrared spectroscopy was used to measure changes in the concentration of cerebral oxyhemoglobin (cO(2)Hb), deoxyhemoglobin (cHHb) and cHbD (the difference between cO(2)Hb and cHHb). In the 141 and the 127 d lambs, changes in MABP and cerebral O(2)-supply were positively linearly related with DeltacO(2)Hb, and negatively with DeltacHHb. MABP was positively linearly related with changes in cHbD. During hemorrhagic hypotension, changes in MABP and cerebral O(2)-supply are reflected by changes in the oxygenation state of cerebral hemoglobin in near-term born lambs.

Effect of des-aspartate-angiotensin I on the actions of angiotensin II in the isolated renal and mesenteric vasculature of hypertensive and STZ-induced diabetic rats.

The present study investigated the action of des-aspartate-angiotensin I (DAA-I) on the pressor action of angiotensin II in the renal and mesenteric vasculature of WKY, SHR and streptozotocin (STZ)-induced diabetic rats. Angiotensin II-induced a dose-dependent pressor response in the renal vasculature. Compared to the WKY, the pressor response was enhanced in the SHR and reduced in the STZ-induced diabetic rat. DAA-I attenuated the angiotensin II pressor action in renal vasculature of WKY and SHR. The attenuation was observed for DAA-I concentration as low as 10(-18) M and was more prominent in SHR. However, the ability of DAA-I to reduce angiotensin II response was lost in the STZ-induced diabetic kidney. Instead, enhancement of angiotensin II pressor response was seen at the lower doses of the octapeptide. The effect of DAA-I was not inhibited by PD123319, an AT2 receptor antagonist, and indomethacin, a cyclo-oxygenase inhibitor in both WKY and SHR, indicating that its action was not mediated by angiotensin AT2 receptor and prostaglandins. The pressor responses to angiotensin II in mesenteric vascular bed were also dose-dependent but smaller in magnitude compared to the renal vasculature. The responses were significantly smaller in SHR but no significant difference was observed between STZ-induced diabetic and WKY rat. Similarly, PD123319 and indomethacin had no effect on the action of DAA-I. The findings reiterate a regulatory role for DAA-I in vascular bed of the kidney and mesentery. By being active at circulating level, DAA-I subserves a physiological role. This function appears to be present in animals with diseased state of hypertension and diabetes. It is likely that DAA-I functions are modified to accommodate the ongoing vascular remodeling.

Pathophysiology of modulation of local glucocorticoid levels by 11beta-hydroxysteroid dehydrogenases.

11beta-Hydroxysteroid dehydrogenases (11beta HSDs) are enzymes that catalyse the interconversion of active glucocorticoids (cortisol and corticosterone) into their inactive 11-keto products (cortisone and 11-deoxycorticosterone). Two isozymes have been identified: 11beta HSD type 1 is a predominant reductase, reactivating glucocorticoids from inert metabolites, whereas 11beta HSD type 2 is a potent dehydrogenase, inactivating glucocorticoids. They play a major role in the modulation of local cortisol levels and hence access of active steroid to corticosteroid receptors. This review focuses on the clinical importance of 11beta HSDs. We describe recent research that has not only advanced our understanding of the physiological role of these enzymes, but also their role in common diseases, including primary obesity and essential hypertension. These data provide encouragement that novel therapies will arise from a fuller understanding of the 11beta HSD system.

Alterations in sodium-potassium regulation in mononuclear leucocytes from young borderline hypertensive and offspring of hypertensive patients.

Membrane ion transports were investigated in lymphocytes from young normotensive and borderline hypertensive offspring with and without heredity for hypertension. Borderline hypertension per se was associated with an enhancement of sodium-potassium pump activity. Heredity per se was associated with increased sodium influx and ouabain-resistant sodium efflux.