6-ketoprostaglandin-f1-alpha and Hypertrophy

Dietary conjugated linoleic acid (CLA) reduces indicators of early renal disease progression and the associated elevated cyclooxygenase (COX) levels in young obese rats with obesity-associated nephropathy (OAN). Therefore, renal function and injury and COX and its metabolites were assessed in obese fa/fa Zucker rats with more advanced renal disease. Obese rats at 16 weeks of age were provided with either cis(c)9, trans(t)11 (fa/fa-9,11) or t10,c12 (fa/fa-10,12) CLA for 8 weeks, and compared to lean (lean-CTL) and obese (fa/fa-CTL) rats provided the control diet without CLA. Obese rats displayed significantly reduced renal function and increased renal injury compared to lean rats. In the obese rat groups, glomerular hypertrophy was reduced in both CLA-supplemented groups. While all other measures of renal function or injury were not different in fa/fa-9,11 compared to fa/fa-CTL rats, the fa/fa-10,12 rats had greater renal hypertrophy, glomerular fibrosis, fibrosis, tubular casts and macrophage infiltration compared to the fa/fa-CTL and fa/fa-9,11 groups. The fa/fa-10,12 group also had elevated levels of renal COX1, which was associated with increased levels of two oxylipins produced by this enzyme, 6-keto-prostaglandin F(1α), and thromboxane B₂. Renal linoleic acid and its lipoxygenase products also were lower in obese compared to lean rats, but CLA supplementation had no effect on these or any other lipoxygenase oxylipins. In summary, supplementation with c9,t11 CLA did not improve more advanced OAN and t10,c12 CLA worsened the renal pathology. Altered production of select COX1 derived oxylipins was associated with the detrimental effect of the t10,c12 isomer.

Topics: 6-Ketoprostaglandin F1 alpha; Aging; Animals; Cyclooxygenase 1; Dietary Supplements; Disease Progression; Fibrosis; Hypertrophy; Kidney; Linoleic Acids, Conjugated; Macrophage Activation; Membrane Proteins; Obesity; Oxylipins; Rats, Zucker; Renal Insufficiency; Severity of Illness Index; Thromboxane B2

Prostacyclin synthase (PGIS) is the final committed enzyme in the metabolic pathway of prostacyclin production. The therapeutic option of intravenous prostacyclin infusion in patients with pulmonary arterial hypertension is limited by the short half-life of the drug and life-threatening catheter-related complications. To develop a better delivery system for prostacyclin, we examined the feasibility of intramuscular injection of an adenoassociated virus (AAV) vector expressing PGIS for preventing monocrotaline-induced pulmonary arterial hypertension in rats. We developed an AAV serotype 1-based vector carrying a human PGIS gene (AAV-PGIS). AAV-PGIS or the control AAV vector expressing enhanced green fluorescent protein was injected into the anterior tibial muscles of 3-week-old male Wistar rats; this was followed by the monocrotaline administration at 7 weeks. Eight weeks after injecting the vector, the plasma levels of 6-keto-prostaglandin F(1alpha) increased in a vector dose-dependent manner. At this time point, the PGIS transduction (1x10(10) genome copies per body) significantly decreased mean pulmonary arterial pressure (33.9+/-2.4 versus 46.1+/-3.0 mm Hg; P<0.05), pulmonary vascular resistance (0.26+/-0.03 versus 0.41+/-0.03 mm Hg x mL(-1) x min(-1) x kg(-1); P<0.05), and medial thickness of the peripheral pulmonary artery (14.6+/-1.5% versus 23.5+/-0.5%; P<0.01) as compared with the controls. Furthermore, the PGIS-transduced rats demonstrated significantly improved survival rates as compared with the controls (100% versus 50%; P<0.05) at 8 weeks postmonocrotaline administration. An intramuscular injection of AAV-PGIS prevents monocrotaline-pulmonary arterial hypertension in rats and provides a new therapeutic alternative for preventing pulmonary arterial hypertension in humans.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Cell Line; Cytochrome P-450 Enzyme System; Dependovirus; Epoprostenol; Feasibility Studies; Gene Transfer Techniques; Genetic Vectors; Heart Rate; Humans; Hypertension, Pulmonary; Hypertrophy; Hypertrophy, Right Ventricular; Injections, Intramuscular; Intramolecular Oxidoreductases; Male; Monocrotaline; Pulmonary Artery; Rats; Rats, Wistar; Survival Analysis

The effect of streptozotocin-induced diabetes mellitus on prostacyclin (PGI2) production by the urinary bladder in rats was investigated. Acute ketotic (two days duration) and non-ketonuric (seven days duration) diabetes had no effect on PGI2 production by the aorta or the bladder. "Chronic" untreated non-ketonuric (62 days duration) diabetes had a marked inhibitory effect on aortic PGI2 secretion which was not observed when rats were treated with insulin. Urinary bladders from animals with "chronic" untreated non-ketonuric diabetes were larger and heavier, and their walls were hypertrophic. The bladders from these latter animals produced more total PGI2, as well as more PGI2 per unit weight. Enhanced PGI2 production by bladders from animals with untreated non-ketonuric diabetes indicates that: 1) severity of the metabolic disturbance due to diabetes mellitus (ketosis) is not as important as the duration of diabetes as far as the induction of changes in PGI2 production is concerned; 2) distension and hypertrophy of the bladder and hyperosmolar urine are probably more potent stimulators of PGI2 production than diabetes is an inhibitor; 3) diabetes mellitus may have a variable effect on PGI2 secretion patterns in different tissues; 4) urinary excretion of PGI2 or its stable metabolite, 6-oxo-PGF1 alpha may not exclusively reflect PGI2 production by systemic vasculature and/or the kidneys; and 5) good control of diabetes prevents the bladder wall and PGI2 synthesis changes.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta, Thoracic; Diabetes Mellitus, Experimental; Diabetic Ketoacidosis; Epoprostenol; Hypertrophy; Male; Radioimmunoassay; Rats; Rats, Inbred Strains; Time Factors; Urinary Bladder