741. Delivery of Human Tissue Kallikrein Gene Mediates Reductions in Blood Pressure and the Levels of Plasma Insulin and Blood Glucose in Fructose-Induced Hypertensive Rats with Diabetes

To determine the relationship between hyperinsulinemia and hypertension in spontaneously hypertensive rats (SHR), the antihyperglycemic agent metformin was administered to SHR and their Wistar-Kyoto (WKY) controls, and its effects on plasma insulin levels and blood pressure were examined. Five-week-old rats were started on oral metformin treatment (350 mg.kg-1.day-1, which was gradually increased to 500 mg.kg-1.day-1 over a 2-wk period). Metformin treatment caused sustained decreases in plasma insulin levels in the SHR (27.1 +/- 2.3 vs. untreated SHR 53.5 +/- 2.7 microU/ml, P < 0.001) without having any effect in the WKY (30.7 +/- 2.2 vs. untreated WKY 37.8 +/- 1.6 microU/ml, P > 0.05). The treatment did not affect the plasma glucose levels in any group. Metformin treatment also attenuated the increase in systolic blood pressure in the SHR (157 +/- 6.0 vs. untreated SHR 196 +/- 9.0 mmHg, P < 0.001) but had no effect in the WKY (134 +/- 3 vs. untreated WKY 136 +/- 4 mmHg, P > 0.05). Furthermore, raising plasma insulin levels in the metformin-treated SHR to levels that existed in the untreated SHR reversed the effect of metformin on blood pressure (189 +/- 3 vs. untreated SHR 208 +/- 5.0 mmHg, P > 0.05). These findings suggest that either hyperinsulinemia may contribute toward the increase in blood pressure in the SHR or that the underlying mechanism is closely associated with the expression of both these disorders.

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Abstract 015: Increased 20-HETE Levels Contribute to Impaired Glucose Metabolism and Type 2 Diabetes in Cyp4a14 Knockout Mice Fed on High Fat Diet.

Hypertension ◽

10.1161/hyp.66.suppl_1.015 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Varunkumar G Pandey ◽

Lars Bellner ◽

Victor Garcia ◽

Joseph Schragenheim ◽

Andrew Cohen ◽

...

Keyword(s):

Insulin Resistance ◽

Blood Pressure ◽

Type 2 Diabetes ◽

Weight Gain ◽

Blood Glucose ◽

High Fat Diet ◽

Plasma Insulin ◽

High Fat ◽

Plasma Insulin Levels

20-HETE (20-Hydroxyeicosatetraenoic acid) is a cytochrome P450 ω-hydroxylase metabolite of arachidonic acid that promotes endothelial dysfunction, microvascular remodeling and hypertension. Previous studies have shown that urinary 20-HETE levels correlate with BMI and plasma insulin levels. However, there is no direct evidence for the role of 20-HETE in the regulation of glucose metabolism, obesity and type 2 diabetes mellitus. In this study we examined the effect of 20-SOLA (2,5,8,11,14,17-hexaoxanonadecan-19-yl-20-hydroxyeicosa-6(Z),15(Z)-dienoate), a water-soluble 20-HETE antagonist, on blood pressure, weight gain and blood glucose in Cyp4a14 knockout (Cyp4a14-/-) mice fed high-fat diet (HFD). The Cyp4a14-/- male mice exhibit high vascular 20-HETE levels and display 20-HETE-dependent hypertension. There was no difference in weight gain and fasting blood glucose between Cyp4a14-/- and wild type (WT) on regular chow. When subjected to HFD for 15 weeks, a significant increase in weight was observed in Cyp4a14-/- as compared to WT mice (56.5±3.45 vs. 30.2±0.7g, p<0.05). Administration of 20-SOLA (10mg/kg/day in drinking water) significantly attenuated the weight gain (28.7±1.47g, p<0.05) and normalized blood pressure in Cyp4a14-/- mice on HFD (116±0.3 vs. 172.7±4.6mmHg, p<0.05). HFD fed Cyp4a14-/- mice exhibited hyperglycemia as opposed to normal glucose levels in WT on a HFD (154±1.9 vs. 96.3±3.0 mg/dL, p<0.05). 20-SOLA prevented the HFD-induced hyperglycemia in Cyp4a14-/- mice (91±8mg/dL, p<0.05). Plasma insulin levels were markedly high in Cyp4a14-/- mice vs. WT on HFD (2.66±0.7 vs. 0.58±0.18ng/mL, p<0.05); corrected by the treatment with 20-SOLA (0.69±0.09 ng/mL, p<0.05). Importantly, glucose and insulin tolerance tests showed impaired glucose homeostasis and insulin resistance in Cyp4a14-/- mice on HFD; ameliorated by treatment with 20-SOLA. This novel finding that blockade of 20-HETE actions by 20-SOLA prevents HFD-induced obesity and restores glucose homeostasis in Cyp4a14-/- mice suggests that 20-HETE contributes to obesity, hyperglycemia and insulin resistance in HFD induced metabolic disorder. The molecular mechanisms underlying 20-HETE mediated metabolic dysfunction are being currently explored.

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Human Tissue Kallikrein Attenuates Hypertension and Secretes into Circulation and Urine After Intramuscular Gene Delivery in Hypertensive Rats

Clinical and Experimental Hypertension ◽

10.3109/10641969909052194 ◽

1999 ◽

Vol 21 (7) ◽

pp. 1145-1160 ◽

Cited By ~ 13

Author(s):

Jenny J. Zhang ◽

Cindy Wang ◽

Kuei-Fu Lin ◽

Lee Chao ◽

Julie Chao

Keyword(s):

Gene Delivery ◽

Human Tissue ◽

Tissue Kallikrein ◽

Hypertensive Rats

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Skeletal muscle sodium and potassium changes after successful surgery in acromegaly: relation to body composition, blood glucose, plasma insulin and blood pressure

Acta Endocrinologica ◽

10.1530/acta.0.1280418 ◽

1993 ◽

Vol 128 (5) ◽

pp. 418-422 ◽

Cited By ~ 12

Author(s):

Kerstin Landin ◽

Björn Petruson ◽

Karl-Erik Jakobsson ◽

Bengt-Åke Bengtsson

Keyword(s):

Blood Pressure ◽

Skeletal Muscle ◽

Body Composition ◽

Blood Glucose ◽

Plasma Insulin ◽

Sodium Content ◽

The Body ◽

Potassium Content ◽

Insulin Levels ◽

Total Body

The aim of this study was to investigate the skeletal muscle sodium/potassium (Na/K) ratio in acromegaly before and 1 year after trans-sphenoidal removal of a growth hormone (GH)-secreting pituitary adenoma. Muscle biopsies were taken and skeletal muscle electrolytes, body composition, glucose, insulin and blood pressure were studied. Fasting blood glucose and plasma insulin levels, but not blood pressure, were higher in acromegalic patients (N = 9) than in controls (N = 6). The skeletal muscle potassium content was higher (p <0.01) but the sodium content and the Na/K ratio were lower (p<0.05 and p<0.001, respectively) in untreated patients with acromegaly as compared to weight-matched healthy controls. Elevated GH, glucose and insulin levels normalized after surgery. Blood pressure remained unchanged. The total body potassium content, the lean body mass and the total body water content decreased and the body fat content increased while the body weight was unchanged. The skeletal muscle potassium content decreased from [median (range)] 9.8 (9.2–11.5) to 7.7 (5.7–9.5) mmol/100 g wet wt (p<0.001). The skeletal muscle sodium content increased from 2.8 (2.5–3.9) to 5.1 (4.3–6.7) mmol/100 g wet wt (p<0.001) and the Na/K ratio increased from 0.28 (0.26–0.38) to 0.56 (0.51–1.18) (p< 0.001) after surgery, which is a higher level than the controls with a Na/K ratio of 0.47 (0.39–0.84) (p<0.01). These changes seem to be mediated by a decreased GH effect on the Na/K pump after successful trans-sphenoidal surgery in acromegaly.

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High-salt diet upregulates kininogen and downregulates tissue kallikrein expression in Dahl-SS and SHR rats

AJP Renal Physiology ◽

10.1152/ajprenal.1996.271.4.f824 ◽

1996 ◽

Vol 271 (4) ◽

pp. F824-F830 ◽

Cited By ~ 5

Author(s):

C. Wang ◽

C. Chao ◽

L. M. Chen ◽

L. Chao ◽

J. Chao

Keyword(s):

Blood Pressure ◽

High Salt ◽

Transcriptional Level ◽

Tissue Kallikrein ◽

Mrna Levels ◽

Hypertensive Rats ◽

High Salt Diet ◽

Salt Loading ◽

Salt Diet ◽

Sd Rats

Tissue kallikrein cleaves low-molecular-weight (low-M(r)) kininogen to produce the vasoactive kinin peptide. It has been suggested that hypertensive patients with low urinary kallikrein excretion may have a defect in sodium handling. In this study, we examined the effect of a high-salt diet on the expression of tissue kallikrein and kininogen genes in Dahl salt-sensitive rats (Dahl-SS), spontaneously hypertensive rats (SHR), and normotensive Sprague-Dawley rats (SD) by Northern and Western blot analysis and radioimmunoassay. Control and experimental groups received normal and high-salt diets containing 0.4% and 8% NaCl, respectively, for 6 wk. High-salt diet induced a significant time-dependent increase of blood pressure in both strains of hypertensive rats and a slight but significant increase of blood pressure in normotensive SD rats. Hepatic kininogen mRNA levels of both Dahl-SS and SHR on a high-salt diet increased 2.4-fold and 2.0-fold, respectively, while alpha 1-antitrypsin mRNA levels were not changed in rats receiving high-salt diet. Immunoreactive total kininogen and low-M(r) kininogen (58 kDa) levels in sera increased in response to high-salt diet in both strains of hypertensive rats. In SD rats, the low-M(r) kininogen level in sera was unaltered, whereas total kininogen increased in response to high-salt diet. Tissue kallikrein mRNAs in the kidney and salivary glands of Dahl-SS, SHR, and SD rats were reduced, whereas beta-actin mRNA was not altered by high-salt diet. Similarly, immunoreactive intrarenal kallikrein levels were reduced in these rats in response to high-salt diet. These studies show that increases in blood pressure after salt loading in Dahl-SS and SHR are accompanied by increases in low-M(r) kininogen. Tissue kallikrein gene expression in hypertensive Dahl-SS and SHR and normotensive SD rats is suppressed after salt loading. These findings show that reduced renal kallikrein expression and increased kininogen expression is regulated at the transcriptional level during salt loading.

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