Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice.

Because polyphenols may have beneficial effects on dyslipidemia, which accelerates atherosclerosis in diabetes, we examined the effect of polyphenols on hepatocellular AMP-activated protein kinase (AMPK) activity and lipid levels, as well as hyperlipidemia and atherogenesis in type 1 diabetic LDL receptor-deficient mice (DMLDLR(-/-)). In HepG2 hepatocytes, polyphenols, including resveratrol (a major polyphenol in red wine), apigenin, and S17834 (a synthetic polyphenol), increased phosphorylation of AMPK and its downstream target, acetyl-CoA carboxylase (ACC), and they increased activity of AMPK with 200 times the potency of metformin. The polyphenols also prevented the lipid accumulation that occurred in HepG2 cells exposed to high glucose, and their ability to do so was mimicked and abrogated, respectively, by overexpression of constitutively active and dominant-negative AMPK mutants.

The thromboxane receptor antagonist S18886 attenuates renal oxidant stress and proteinuria in diabetic apolipoprotein E-deficient mice.

Arachidonic acid metabolites, some of which may activate thromboxane A(2) receptors (TPr) and contribute to the development of diabetes complications, including nephropathy, are elevated in diabetes. This study determined the effect of blocking TPr with S18886 or inhibiting cyclooxygenase with aspirin on oxidative stress and the early stages of nephropathy in streptozotocin-induced diabetic apolipoprotein E(-/-) mice. Diabetic mice were treated with S18886 (5 mg .

The thromboxane A2 receptor antagonist S18886 prevents enhanced atherogenesis caused by diabetes mellitus.

Background: S18886 is an orally active thromboxane A2 (TXA2) receptor (TP) antagonist in clinical development for use in secondary prevention of thrombotic events in cardiovascular disease. We previously showed that S18886 inhibits atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice by a mechanism independent of platelet-derived TXA2. Atherosclerosis is accelerated by diabetes and is associated with increased TXA(2) and other eicosanoids that stimulate TP.

AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells.

The antidiabetic drug metformin stimulates AMP-activated protein kinase (AMPK) activity in the liver and in skeletal muscle. To better understand the role of AMPK in the regulation of hepatic lipids, we studied the effect of metformin on AMPK and its downstream effector, acetyl-CoA carboxylase (ACC), as well as on lipid content in cultured human hepatoma HepG2 cells. Metformin increased Thr-172 phosphorylation of the alpha subunit of AMPK in a dose- and time-dependent manner.

The diabetic nephropathy and the development of hypertension in rats.

The present study was designed to examine the development of hypertension in diabetic rats treated with streptozotocin (STZ, 1 mg/g bw). The rats were studied at 3, 6, 9, 12 and 15 weeks. From the third week the rats were divided in diabetic rats according their glycemias and controls, along 15 weeks.

Renal function in the diabetic pregnant rats.

Diabetic nephropathy is associated with increased urinary albumin and reduce kallikrein excretion. Increased activity of the renal kallikrein-kinin system has been suggested as one of the possible mechanisms underlying diabetic hyperfiltration. The present study shown that the Kallikrein-kinin system is progressively increased in the diabetic-pregnant rats at 7, 14, 21 days; 48 and 7 days after pregnancy (P < 0.

Kallikrein-like amidase activity in renal ischemia and reperfusion.

We assessed a kallikrein-like amidase activity probably related to the kallikrein-kinin system, as well as the participation of leukocyte infiltration in renal ischemia and reperfusion. Male C57BL/KSJmdb mice were subjected to 20 or 60 min of ischemia and to different periods of reperfusion. A control group consisted of sham-operated mice, under similar conditions, except for ischemia induction.

The involvement of kallikrein-kinin system in diabetes type I (insulitis).

Islet inflammation or insulitis is followed by selective destruction of the insulin secreting B-cell. Animal models of insulin-dependent diabetes mellitus (IDDM) have been used to characterize more fully insulitis, and our results with C57/BL/Ks mdb with low doses of streptozotocin (STZ) confirmed the disease. B1 receptor antagonist [Leu8]des-Arg9-BK has shown a significant effect on diabetic glycemia and renal control parameters.

Renal ischemia-induced increase in vascular permeability is limited by hypothermia.

The purpose of the present work was to evaluate the kallikrein-kinin system and effects of hypothermia during renal ischemia and reperfusion. Male C57BL/KSJmdb mice were subjected to 20 or 60 min ischemia for different periods of reperfusion. Our results demonstrate that short periods of ischemia followed by reperfusion did not cause significant alterations in kallikrein activity, Evans Blue (EB) extravasation, prokallikreins, myeloperoxidase activity or plasma creatinine concentration.

Effects of aprotinin on the kallikrein-kinin system in type I diabetes (insulitis).

Sub-diabetogenic doses of streptozotocin (STZ) produce insulitis, beta cell destruction and diabetes in mice. Since kinin have been proposed as an inflammatory mediator in several diseases, we decided to evaluate the role of the kallikrein-kinin system in the evolution of insulitis. Male C 57 BL/KsJ mdb mice were injected with STZ (40 mg/kg) for 5 consecutive d.

Effects of B1 and B2 kinin receptor antagonists in diabetic mice.

Streptozotocin (STZ) has been extensively used to produce type I diabetes in animals. This experimental disease is characterized by a mild inflammatory reaction in the Langerhans islets. Because kinins have been proposed as prominent inflammatory mediators in the pathogenesis of several diseases, we decided to evaluate the role of kinins and their receptors in the evolution of insulitis.

Effects of HOE 140 on some renal functions in type I diabetic mice.

To investigate in mice the mechanisms underlying renal functions in a type I diabetes model, we have suppressed B2 kinin receptors local activities by their specific antagonist D-Arg [Hyp3-Thi5-D-Tic7-Oic8]BK (HOE 140). Mice made diabetic with low consecutive doses of streptozotocin (STZ) (45 mg/k BW during 5 days) were injected with HOE 140 (15 micrograms/twice a day) for 15 days. This drug did not modify glycemia of STZ treated animals but a significantly reduction of urinary proteins, nitrites and kallikrein was observed.

Streptozotocin-induced hyperglycemia is decreased by nitric oxide inhibition.

1. Diabetes mellitus type I was induced in 3-month old male C57 BL/KS-mdb mice (N = 24) by ip injection of streptozotocin (STZ, 45 mg/kg body weight) for 5 days. 2.

The kallikrein-kinin system in early state of diabetes.

The kallikrein-kinin system was studied in 9 normals, healthy subjects (6 men, 3 women, age range 1 to 14 years) and 15 diabetic patients (9 men, 6 women age range 2 to 14 years) with an evolution of the disease between 1 to 14 years. Diabetic patients with low microalbuminuria (6.62 +/- 0.

The kallikrein-kinin system in the colon and lung fluid from a cribriform degeneration (cri) mutant mouse.

The cribriform degeneration (cri) mutant mouse was widely studied in regard to the electrolyte and kallikrein metabolism because of its potentiality as a cystic fibrosis (CF) genetic animal model. In this paper the activity of the kallikrein-kinin system, and the kininase activity and glycoproteins concentration in colon and pulmonary lavage fluid (PLF) in homozygous mutant (cri/cri) and control sibling mice are described. The mutant mice showed a diminished kininogenase and kininase activity and glycoproteins concentrations in both studied organs.