8-epi-prostaglandin-f2alpha and Albuminuria

The primary goals were to re-examine whether sevelamer carbonate (SC) reduces advanced glycation end products (AGEs) (methylglyoxal and carboxymethyllysine [CML]), increases antioxidant defenses, reduces pro-oxidants, and improves hemoglobin A1c (HbA1c) in patients with type 2 diabetes mellitus (T2DM) and diabetic kidney disease (DKD). Secondary goals examined albuminuria, age, race, sex, and metformin prescription.. This two-center, randomized, intention-to-treat, open-label study evaluated 117 patients with T2DM (HbA1c >6.5%) and stages 2-4 DKD (urinary albumin/creatinine ratio ≥200 mg/g) treated with SC (1600 mg) or calcium carbonate (1200 mg), three times a day, without changing medications or diet. Statistical analyses used linear mixed models adjusted for randomization levels. Preselected subgroup analyses of sex, race, age, and metformin were conducted.. SC lowered serum methylglyoxal (95% confidence interval [CI], -0.72 to -0.29; P<0.001), serum CML (95% CI, -5.08 to -1.35; P≤0.001), and intracellular CML (95% CI, -1.63 to -0.28; P=0.01). SC increased anti-inflammatory defenses, including nuclear factor like-2 (95% CI, 0.58 to 1.29; P=0.001), AGE receptor 1 (95% CI, 0.23 to 0.96; P=0.001), NAD-dependent deacetylase sirtuin-1 (95% CI, 0.20 to 0.86; P=0.002), and estrogen receptor α (95% CI, 1.38 to 2.73; P ≤0.001). SC also decreased proinflammatory factors such as TNF receptor 1 (95% CI, -1.56 to -0.72; P≤0.001) and the receptor for AGEs (95% CI, -0.58 to 1.53; P≤0.001). There were no differences in HbA1c, GFR, or albuminuria in the overall group. Subanalyses showed that SC lowered HbA1c in women (95% CI, -1.71 to -0.27; P=0.01, interaction P=0.002), and reduced albuminuria in those aged <65 years (95% CI, -1.15 to -0.07; P=0.03, interaction P=0.02) and non-Caucasians (95% CI, -1.11 to -0.22; P=0.003, interaction P≤0.001), whereas albuminuria increased after SC and calcium carbonate in Caucasians.. SC reduced circulating and cellular AGEs, increased antioxidants, and decreased pro-oxidants, but did not change HbA1c or the albumin/creatinine ratio overall in patients with T2DM and DKD. Because subanalyses revealed that SC may reduce HbA1c and albuminuria in some patients with T2DM with DKD, further studies may be warranted.

Topics: Adiponectin; Age Factors; Aged; Albuminuria; Chelating Agents; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Estrogen Receptor alpha; Female; Glycated Hemoglobin; Glycation End Products, Advanced; Humans; Hypoglycemic Agents; Intention to Treat Analysis; Lysine; Male; Metformin; Middle Aged; NF-E2-Related Factor 2; Pyruvaldehyde; Receptor for Advanced Glycation End Products; Receptors, Tumor Necrosis Factor, Type I; RNA, Messenger; Sevelamer; Sex Factors; Single-Blind Method; Sirtuin 1; White People

We aimed to test the hypothesis that the angiotensin II receptor blocker (ARB)/diuretic combination decreases the urinary albumin/creatinine ratio (UACR) to a greater extent than treatment with the ARB/calcium-channel blocker (CCB) combination through a mechanism related to a greater reduction of sleep blood pressure (BP).. We conducted a prospective, randomized, open-label, blinded end-point trial in hypertensive patients. Patients received olmesartan monotherapy for 12 weeks, followed by an additional use of hydrochlorothiazide (HCTZ) (n = 104) or azelnidipine (n = 103) for 24 weeks after randomization. The measurements of central and ambulatory BP, and laboratory tests were performed at baseline and the end of the study.. The adjusted percent reduction in UACR in the olmesartan/HCTZ group was significantly greater than that in the olmesartan/azelnidipine group (-43.2 vs. -24.0%, P = 0.0014), although the olmesartan/azelnidipine group showed greater decreases in central systolic BP (SBP; P = 0.04), oxidative stress (urinary 8-isoprostane; P = 0.02), inflammation (high-sensitivity C-reactive protein; P = 0.04), and insulin resistance (the homeostasis model assessment insulin resistance index (HOMA(IR)); P < 0.001) than the olmesartan/HCTZ group. In multivariate regression analyses, the significant determinants of change in UACR in the olmesartan/HCTZ group were changes in sleep SBP (P < 0.001), central SBP (P = 0.01), estimated glomerular filtration rate (eGFR) (P = 0.02), and HOMA(IR) (P = 0.03), and those in the olmesartan/azelnidipine group were changes in central SBP (P = 0.001) and urinary 8-isoprostane (P = 0.02).. These data showed that the ARB/diuretic combination decreased UACR significantly more than the ARB/CCB combination, and this decrease in UACR was associated with a greater magnitude reduction in sleep SBP.

Topics: Adult; Aged; Aged, 80 and over; Albuminuria; Angiotensin Receptor Antagonists; Azetidinecarboxylic Acid; Blood Pressure; C-Reactive Protein; Calcium Channel Blockers; Creatinine; Dihydropyridines; Dinoprost; Diuretics; Female; Humans; Imidazoles; Male; Middle Aged; Sleep; Tetrazoles

Platelet activation is persistently enhanced, and its inhibition by low-dose aspirin is impaired in type 2 diabetes mellitus. We investigated in vivo thromboxane (TX) and prostacyclin (PGI2) biosynthesis and their determinants, as well as aspirin responsiveness, in young adult subjects with type 1 diabetes mellitus (T1DM) without overt cardiovascular disease and stable glycemic control. The biosynthesis of TXA2 was persistently increased in subjects with T1DM versus matched healthy subjects, with females showing higher urinary TX metabolite (TXM) excretion than male subjects with T1DM. Microalbuminuria and urinary 8-iso-PGF2α, an index of in vivo oxidative stress, independently predicted TXM excretion in T1DM. No homeostatic increase in PGI2 biosynthesis was detected. Platelet COX-1 suppression by low-dose aspirin and the kinetics of its recovery after drug withdrawal were similar in patients and control subjects and were unaffected by glucose variability. We conclude that patients with T1DM and stable glycemic control display enhanced platelet activation correlating with female sex and microvascular and oxidative damages. Moreover, aspirin responsiveness is unimpaired in T1DM, suggesting that the metabolic disturbance per se is unrelated to altered pharmacodynamics. The efficacy and safety of low-dose aspirin in T1DM warrant further clinical investigation.

Topics: Adult; Albuminuria; Aspirin; Blood Glucose; Cross-Sectional Studies; Cyclooxygenase 1; Diabetes Mellitus, Type 1; Dinoprost; Epoprostenol; Female; Humans; Male; Matched-Pair Analysis; Microvessels; Middle Aged; Oxidative Stress; Platelet Activation; Platelet Aggregation Inhibitors; Sex Factors; Thromboxane A2

The concentration of adenosine in the normal kidney increases markedly during renal hypoxia, ischemia, and inflammation. A recent study reported that an A3 adenosine receptor (A3AR) antagonist attenuated the progression of renal fibrosis. The adriamycin (ADX)-induced nephropathy model induces podocyte injury, which results in severe proteinuria and progressive glomerulosclerosis. In this study, we investigated the preventive effect of a highly selective A3AR antagonist (LJ1888) in ADX-induced nephropathy. Three groups of six-week-old Balb/c mice were treated with ADX (11 mg/kg) for four weeks and LJ1888 (10 mg/kg) for two weeks as following: 1) control; 2) ADX; and 3) ADX + LJ1888. ADX treatment decreased body weight without a change in water and food intake, but this was ameliorated by LJ1888 treatment. Interestingly, LJ1888 lowered plasma creatinine level, proteinuria, and albuminuria, which had increased during ADX treatment. Furthermore, LJ1888 inhibited urinary nephrin excretion as a podocyte injury marker, and urine 8-isoprostane and kidney lipid peroxide concentration, which are markers of oxidative stress, increased after injection of ADX. ADX also induced the activation of proinflammatory and profibrotic molecules such as TGF-β1, MCP-1, PAI-1, type IV collagen, NF-κB, NOX4, TLR4, TNFα, IL-1β, and IFN-γ, but they were remarkably suppressed after LJ1888 treatment. In conclusion, our results suggest that LJ1888 has a renoprotective effect in ADX-induced nephropathy, which might be associated with podocyte injury through oxidative stress. Therefore, LJ1888, a selective A3AR antagonist, could be considered as a potential therapeutic agent in renal glomerular diseases which include podocyte injury and proteinuria.

Topics: Actins; Adenosine; Adenosine A3 Receptor Antagonists; Albuminuria; Animals; Body Weight; Creatinine; Dinoprost; Disease Models, Animal; Doxorubicin; Immunohistochemistry; Kidney; Kidney Diseases; Lipid Peroxidation; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; NF-kappa B; Oxidative Stress; Plasminogen Activator Inhibitor 1; Proteinuria; Transforming Growth Factor beta1

Piperidine-based peroxisome proliferator-activated receptor-α agonists are agents that are efficacious in improving lipid, glycemic, and inflammatory indicators in diabetes and obesity. This study sought to determine whether CP-900691 ((S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP), a member of this novel class of agents, by decreasing plasma triglycerides, could prevent diabetic nephropathy in the Black and Tan, BRachyuric (BTBR) ob/ob mouse model of type 2 diabetes mellitus. Four-week old female BTBR WT and BTBR ob/ob mice received either regular chow or one containing CP (3 mg/kg per day) for 14 weeks. CP elevated plasma high-density lipoprotein, albuminuria, and urinary excretion of 8-epi PGF(2α), a product of the nonenzymatic metabolism of arachidonic acid and whose production is elevated in oxidative stress, in BTBR WT mice. In BTBR ob/ob mice, CP reduced plasma triglycerides and non-esterified fatty acids, fasting blood glucose, body weight, and plasma interleukin-6, while concomitantly improving insulin resistance. Despite these beneficial metabolic effects, CP had no effect on elevated plasma insulin, 8-epi PGF(2α) excretion, and albuminuria, and surprisingly, did not ameliorate the development of diabetic nephropathy, having no effect on the accumulation of renal macrophages, glomerular hypertrophy, and increased mesangial matrix expansion. In addition, CP did not increase plasma high-density lipoprotein in BTBR ob/ob mice, while paradoxically increasing total cholesterol levels. These findings indicate that 8-epi PGF(2α), possibly along with hyperinsulinemia and inflammatory and dysfunctional lipoproteins, is integral to the development of diabetic nephropathy and should be considered as a potential target of therapy in the treatment of diabetic nephropathy.

Topics: Albuminuria; Animals; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Disease Progression; Female; Glomerular Mesangium; Hypercholesterolemia; Hypertriglyceridemia; Hypertrophy; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Kidney; Mice; Mice, Inbred Strains; Mice, Obese; Obesity; Piperidines; PPAR alpha; Propionates

To investigate the changes of serum anti-aging protein Klotho and neutrophil gelatinase-associated lipocalin (NGAL) levels and their correlation in type 2 diabetes mellitus (T2DM) patients at different stages of diabetic kidney disease (DKD) determined by urinary albuminuria.. 462 cases with T2DM were divided into three groups: normoalbuminuric [N-UAlb; urinary albumin to creatinine ratio (UACR) < 30 mg/g, n=180], microalbuminuric [M-UAlb; UACR 30-300 mg/g, n = 158], macroalbuminuric [L-UAlb; UACR > 300 mg/g, n = 124]. The levels of serum soluble-Klotho (sKlotho), NGAL, 8-isoprostane prostaglandin F2α (8-iso-PGF2α), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1) were determined by enzyme-linked immunosorbent assay (ELISA) in all cases and 160 control subjects.. Compared with control, serum sKlotho levels were significantly decreased (P < 0.001), and serum NGAL levels increased significantly (P < 0.001) in T2DM patients. Furthermore, serum sKlotho and NGAL levels were significantly negatively correlated (P < 0.001). Serum sKlotho levels negatively correlated with UACR, TG, CHO, LDL, 8-Iso-PGF2α, MCP-1, TNF-α, TGF-β1 (P < 0.001), but positively correlated with LDL (P < 0.001). Serum NGAL levels positively correlated with UACR, 8-Iso-PGF2α, MCP-1, TNF-α, TGF-β1 (P < 0.001). In addition, serum NGAL levels and LDL were significantly positively correlated (P = 0.005), and HDL was significantly negatively correlated (P < 0.001).. Serum Klotho and NGAL levels may become new biomarkers of the early diagnosis of DKD in T2DM. Klotho may participate in the development of DKD pathological mechanism such as oxidative stress related to inflammation, renal fibrosis, lipid metabolic disorders, modulating the pathological process of diabetic kidney tissue. NGAL may play a part in these mechanisms.

Topics: Acute-Phase Proteins; Adult; Albuminuria; Biomarkers; Case-Control Studies; Chemokine CCL2; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Disease Progression; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Female; Glucuronidase; Humans; Klotho Proteins; Lipocalin-2; Lipocalins; Male; Middle Aged; Proto-Oncogene Proteins; Serum Albumin; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

The augmentation index (AIx) indicates arterial wave reflection. Clinical studies have shown a relationship between an elevated AIx and cardiovascular disease. This cross-sectional study attempted to clarify the clinical significance of AIx in patients with preserved kidney function.. The subjects were 321 patients with preserved kidney function (an estimated glomerular filtration rate ≥60 mL/min/1.73 m2 and normoalbuminuria) but with no history of cardiovascular events. The AIx was determined in the radial artery by means of tonometry, and the relationships of the AIx to kidney function and markers of atherosclerosis were examined.. A significant positive correlation (r=0.30; p<0.001) was found between the AIx and the urinary albumin concentration. The AIx showed a significant positive correlation (r=0.28; p<0.001) with the serum high-sensitivity C-reactive protein concentration, as a marker of inflammation; with the urinary 8-iso-prostaglandin F2α concentration (r=0.31; p<0.001), as a marker of oxidative stress; and with the cardio-ankle vascular index (r=0.17; p<0.01), as a marker of systemic arterial stiffness. Multiple regression analysis indicated that the urinary 8-iso-prostaglandin F2α concentration (t=5.1; p<0.001), serum high-sensitivity C-reactive protein concentration (t=4.9; p<0.001), and urinary albumin concentration (t=3.6; p<0.01) were independent variables for AIx after adjustment.. These findings indicate that the AIx reflects inflammation, oxidative stress, and the urinary albumin concentration in patients with preserved kidney function.

Topics: Aged; Aged, 80 and over; Albuminuria; Blood Pressure; C-Reactive Protein; Cross-Sectional Studies; Dinoprost; Female; Glomerular Filtration Rate; Humans; Inflammation; Kidney; Male; Manometry; Middle Aged; Multivariate Analysis; Oxidative Stress; Radial Artery; Regression Analysis

We assessed the relative contribution of the mitochondrial respiratory chain and NADPH (nicotinamide adenine dinucleotide phosphate) oxidase to deoxycorticosterone acetate (DOCA)-salt hypertension in mice. The daily mean arterial pressure was monitored by radiotelemetry in DOCA-salt-treated mice given vehicle or the mitochondrial respiratory chain complex I inhibitor rotenone. This treatment produced remarkable attenuation of DOCA-salt hypertension. Similar results were obtained with other inhibitors of mitochondrial function, including 5-hydroxydecanoate (specific for mitochondrial potassium-ATP channels), benzylguanidine (complexes I and III), and the cell-permeable manganese tetrakis (4-benzoic acid) porphyrin (a mimic of mitochondrial superoxide dismutase). In parallel with the blood pressure-lowering effect of rotenone, the DOCA-salt-induced increases in urinary 8-isoprostane excretion and in reactive oxygen species production of isolated kidney mitochondria were both significantly attenuated. Conversely, the DOCA-salt-induced reduction of urinary nitrate/nitrite excretion was significantly elevated. Following DOCA-salt treatment, mice deficient in NADPH oxidase subunits gp91(phox) or p47(phox) exhibited a partial attenuation of the hypertensive response at early but not later time points. Thus, the mitochondrial respiratory chain is a major source of oxidative stress in DOCA-salt hypertension, whereas NADPH oxidase may have a relatively minor role during the early stage of hypertension.

Topics: Acetophenones; Albuminuria; Aldosterone; Animals; Blood Pressure; Cell Line; Desoxycorticosterone; Dinoprost; Electron Transport; Enzyme Inhibitors; Humans; Hypertension; Male; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Myocytes, Smooth Muscle; NADPH Oxidase 2; NADPH Oxidases; Nitrogen Oxides; Oxidative Stress; Rotenone; Sodium Chloride

It has been reported that urinary oxidative stress markers are higher in diabetic patients with proteinuria. We performed the present study to elucidate the relationship between urinary excretion of oxidative stress markers, albumin excretion, and histological changes, and to confirm the potential utility of oxidative stress markers for clinical treatment.. Diabetic db/db mice or nondiabetic db/m mice were administered candesartan (10 mg/kg/day) or hydralazine (50 mg/kg/day) for 18 weeks.. Thirty-week-old male db/db mice treated with control vehicle revealed elevated urinary excretion and immunohistological levels of 8-hydroxydeoxyguanosine in glomeruli when compared to db/m mice. Treatment with candesartan, but not hydralazine, reduced these values to levels in db/m mice. Increased mesangial expansion, urinary excretion of albumin and 8-isoprostane, and glomerular immunohistological levels of nitrotyrosine in db/db mice were also decreased markedly by candesartan but not hydralazine. Interestingly, correlations between levels of albumin and oxidative stress markers in urine were very high, even when groups undergoing long-term (44 weeks) treatment were included (correlation coefficient 0.767 with respect to 8-hydroxydeoxyguanosine, 0.888 with respect to 8-isoprostane).. It is anticipated that urinary concentrations of oxidative stress markers will be direct barometers of glomerulus-derived oxidative stress and glomerular injury in diabetic nephropathy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Benzimidazoles; Biomarkers; Biphenyl Compounds; Deoxyguanosine; Diabetes Mellitus; Diabetic Nephropathies; Dinoprost; Disease Models, Animal; Hydralazine; Kidney Glomerulus; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Tetrazoles; Treatment Outcome; Tyrosine

The C57Bl/6J mouse strain, the genetic background of many transgenic and gene knockout models, is salt sensitive and resistant to renal injury. We tested the hypothesis that renal dopaminergic function is defective in C57Bl/6J mice. On normal NaCl (0.8%, 1 wk) diet, anesthetized and conscious (telemetry) blood pressures were similar in C57Bl/6J and SJL/J mice. High NaCl (6%, 1 wk) increased blood pressure (approximately 30%) in C57Bl/6J but not in SJL/J mice and urinary dopamine to greater extent in SJL/J than in C57Bl/6J mice. Absolute and fractional sodium excretions were lower in SJL/J than in C57Bl/6J mice. The blood pressure-natriuresis plot was shifted to the right in C57Bl/6J mice. Renal expressions of D(1)-like (D(1)R and D(5)R) and angiotensin II AT(1) receptors were similar on normal salt, but high salt increased D(5)R only in C57Bl/6J. GRK4 expression was lower on normal but higher on high salt in C57Bl/6J than in SJL/J mice. Salt increased the excretion of microalbumin and 8-isoprostane (oxidative stress marker) and the degree of renal injury to a greater extent in SJL/J than in C57Bl/6J mice. A D(1)-like receptor agonist increased sodium excretion whereas a D(1)-like receptor antagonist decreased sodium excretion in SJL/J but not in C57Bl/6J mice. In contrast, parathyroid hormone had a similar natriuretic effect in both strains. These results show that defective D(1)-like receptor function is a major cause of salt sensitivity in C57Bl/6J mice, decreased renal dopamine production might also contribute. The relative resistance to renal injury of C57Bl/6J may be a consequence of decreased production of reactive oxygen species.

Topics: Albuminuria; Animals; Benzazepines; Blood Pressure; Dinoprost; Dopamine; Dopamine Agonists; Dopamine Antagonists; Fenoldopam; Genotype; Kidney; Male; Mice; Mice, Inbred C57BL; Natriuresis; Oxidative Stress; Parathyroid Hormone; Phenotype; Receptor, Angiotensin, Type 1; Receptors, Dopamine D1; Receptors, Dopamine D5; Sodium Chloride, Dietary; Species Specificity

Although it has been reported that angiotensin II receptor blockers inhibited the formation and accumulation of advanced glycation endproducts (AGEs) in vitro and in vivo, whether they can do so clinically is not clear. We investigated the effects of 12-month valsartan therapy on various markers of inflammation, glycation, and oxidation in type 2 diabetic subjects with hypertension. We started 40 mg/day valsartan treatment in 15 type 2 diabetic patients with hypertension. In 6 patients, the dose of valsartan was increased to 80 mg/day after 6 months and maintained until 12 months. Metabolic parameters including BMI and serum high molecular weight (HMW)-adiponectin, high-sensitivity C-reactive protein (hs-CRP) as an inflammation marker, AGEs, paraoxonase activity, platelet-activating factor (PAF)- acetylhydrolase activity, and urine 8-isoprostane levels were measured at baseline and after 6 and 12 months of treatment. Urine microalbumin level and carotid artery intima-media thickness (IMT) were also measured. Even after valsartan therapy, the blood pressure levels of the patients were not decreased significantly. Serum AGEs and urine 8-isoprostane levels decreased at both 6 and 12 months (P < 0.05 for both), although other metabolic and oxidative markers were unchanged. Though urine microalbumin levels tended to be decreased after 6 and 12 months of valsartan treatment, the changes were not significant. Mean IMT at 12 months was not changed from the baseline value. In conclusion, the findings suggest that treatment with valsartan, even at a low dose, may ameliorate some glycation and oxidative stress markers independently of an effect on blood pressure in hypertensive type 2 diabetic subjects.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Adiponectin; Aged; Albuminuria; Antihypertensive Agents; Aryldialkylphosphatase; Biomarkers; C-Reactive Protein; Carotid Arteries; Diabetes Mellitus, Type 2; Dinoprost; Female; Glycation End Products, Advanced; Humans; Hypertension; Male; Middle Aged; Oxidative Stress; Tetrazoles; Valine; Valsartan

Recent studies have uncovered various pleiotrophic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase-inhibiting drugs (statins). Several studies have identified a beneficial effect of statins on diabetic nephropathy; however, the molecular mechanisms are unclear. In this study, we show that statin ameliorates nephropathy in db/db mice, a rodent model of type 2 diabetes, via downregulation of NAD(P)H oxidase NOX4, which is a major source of oxidative stress in the kidney. Pitavastatin treatment for 2 weeks starting at 12 weeks of age significantly reduced albuminuria in the db/db mice concomitant with a reduction of urinary 8-hydroxy-2'-deoxyguanosine and 8-epi-prostaglandin F(2alpha). Immunohistochemical analysis found increased amounts of 8-hydroxy-2'-deoxyguanosine and NOX4 protein in the kidney of db/db mice. Quantitative reverse transcription-polymerase chain reaction also showed increased levels of NOX4 mRNA. Pitavastatin normalized all of these changes in the kidneys of diabetic animals. Additionally, 12-week treatment with the statin completely normalized the levels of transforming growth factor-beta1 and fibronectin mRNA as well as the mesangial expansion characteristic of diabetic nephropathy. Our study demonstrates that pitavastatin ameliorates diabetic nephropathy in db/db mice by minimizing oxidative stress by downregulating NOX4 expression. These findings may provide insight into the mechanisms of statin therapy in early stages of diabetic nephropathy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Albuminuria; Animals; Blood Glucose; Body Weight; Cell Proliferation; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Disease Models, Animal; Down-Regulation; Fibronectins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids; Male; Mesangial Cells; Mice; NADPH Oxidase 4; NADPH Oxidases; Oxidative Stress; Quinolines; RNA, Messenger; Time Factors; Transforming Growth Factor beta1

Dietary lipids are reported to affect the blood pressure in both humans and experimental animal models with hypertension. In the present study, 2-kidney, 1-clip (2K1C) hypertensive rats were treated with the modified fatty acid tetradecylthioacetic acid (TTA) from the time of clipping or after hypertension was established. TTA treatment attenuated the development of hypertension and reduced established 2K1C hypertension. The mRNA level of renin in the clipped kidney and the plasma renin activity were markedly reduced, and the plasma angiotensin II level tended to decrease after TTA treatment. In addition, TTA reduced the mRNA level of angiotensinogen in white adipose tissue. Prevention of organ damage was demonstrated by normal urinary excretion of protein, maintained serum albumin, lower heart weight, and clearly reduced vascular, glomerular, and tubulointerstitial damage in the nonclipped kidney. Renal function was not affected as estimated by unchanged plasma creatinine. Furthermore, the serum levels of triacylglycerol and cholesterol were reduced by TTA. The serum fatty acid composition was changed, resulting in a favorable increase of oleic acid. However, the levels of all of the omega-3 fatty acids and of linoleic acid were reduced, and no change was seen in the level of arachidonic acid, but the urinary excretion of 8-iso-prostaglandin F2alpha was declined. In conclusion, TTA attenuated the development of hypertension, reduced established hypertension, and prevented the development of organ damage in 2K1C rats, possibly by reducing the amounts of the vasoconstrictors angiotensin II and 8-iso-prostaglandin F2alpha and by inducing a favorable increase of oleic acid in serum.

Topics: Albuminuria; Angiotensin II; Animals; Blood Vessels; Dinoprost; Fatty Acids; Hypertension, Renovascular; Kidney; Liver; Male; Oleic Acid; Proteinuria; Rats; Rats, Wistar; Renin; RNA, Messenger; Sulfides; Vasoconstrictor Agents