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1.
Cell Mol Biol (Noisy-le-grand) ; 51(6): 539-45, 2005 Nov 08.
Article in English | MEDLINE | ID: mdl-16309578

ABSTRACT

Intrarenal concentration of angiotensin II increases after the onset of ureteral obstruction in the obstructed kidney. The effect of pretreatment with losartan, a specific angiotensin II AT1 receptor antagonist, on lipid contents, which were previously modified by unilateral ureteral obstruction (UUO), was studied in renal cortex of rats. Adult Wistar Kyoto rats were subjected to either UUO for 24 hr or control sham operation after being treated with losartan in the drinking water at 10 mg/kg rat/day for 15 days. In the cortex of obstructed kidney the increased free and esterified cholesterol concentrations were associated with the increased cholesterol synthesis measured by incorporation of 14C-acetate (0.001>p), compared with control and contralateral kidneys. The increased amount of phosphatidylcholine was related with the increased incorporation of 14C-choline into phosphatidylcholine (0.01>p). Phosphatidylethanolamine and sphingomyelin decreased slightly but total phospholipid content did not change. The level of AT1 receptor mRNA in obstructed kidney was significantly lower than in control and contralateral kidneys. Losartan pretreatment attenuated (0.01>p) the increase in cholesterol content and synthesis and restored and enhanced the AT1 angiotensin II receptor gene expression. The interference in the renin-angiotensin system before UUO may modify renal cortex cholesterol content.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/pharmacology , Kidney Cortex/metabolism , Lipid Metabolism/drug effects , Lipids/analysis , Losartan/pharmacology , Ureteral Obstruction/metabolism , Angiotensin II/metabolism , Animals , Cholesterol/metabolism , Fatty Acids/metabolism , Female , Gene Expression Regulation/drug effects , Gene Expression Regulation/physiology , Kidney Cortex/drug effects , Kidney Cortex/physiopathology , Phosphatidylcholines/metabolism , Phosphatidylethanolamines/metabolism , RNA, Messenger/analysis , Rats , Rats, Inbred WKY , Receptor, Angiotensin, Type 1/analysis , Receptor, Angiotensin, Type 1/genetics , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , Sphingomyelins/metabolism
2.
Cell Mol Biol (Noisy-le-grand) ; 51(6): 547-55, 2005 Nov 08.
Article in English | MEDLINE | ID: mdl-16309579

ABSTRACT

Angiotensin II, a profibrotic cytokine, plays a main role in the initiation of renal fibrogenesis at a very early stage leading to a progressive loss of renal function in unilateral ureteral obstruction (UUO). We studied the involvement of AT1 angiotensin II receptor in the physiopathology of tubulointerstitial fibrosis in UUO, focusing in the regulation of the oxidative stress state and in the HSP 70 expression, in renal tissue. UUO or control sham operation was perform to Wistar Kyoto rats after being treated with the AT1 angiotensin II receptor antagonist Losartan (10 mg/kg/day) in the drinking water for 15 days. Twenty four hours later, mRNA AT1 receptor expression was studied. Renal fibrosis was evaluated through TGFbeta expression and superoxide dismutase (SOD) activity, hydroxyl radicals, O2- and total antioxidant activity were measured by spectrophotometric assay. Immunohistochemical and Western blot analysis of HSP 70 were performed. A non-hypotensive dose of Losartan significantly down regulated the expression of AT1 receptor. Prevention of renal fibrogenesis by Losartan treatment was demonstrated by TGFbeta mRNA expression similar to control. Oxidative stress in obstructed kidney was evident since a decreased SOD activity and a two-fold increase in the concentration of hydroxyl radicals and O2- was observed when compared to the control. Losartan produced down regulation of ROS with recovery of the SOD activity and higher expression of HSP 70 compared to obstructed kidney of rats receiving vehicle. We can conclude that after 24 hr of UUO, protection against tubulointerstitial fibrosis by Losartan, independent from changes in blood pressure, includes decreased oxidative stress linked to upregulation of HSP 70 expression.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/pharmacology , Gene Expression Regulation/drug effects , HSP70 Heat-Shock Proteins/genetics , Losartan/pharmacology , Oxidative Stress/drug effects , Ureteral Obstruction/metabolism , Animals , Blood Pressure/drug effects , Blood Pressure/physiology , Female , Fibrosis/pathology , Fibrosis/physiopathology , HSP70 Heat-Shock Proteins/biosynthesis , Hydroxyl Radical/analysis , Immunohistochemistry , Kidney Cortex/metabolism , Kidney Cortex/pathology , Kidney Cortex/physiopathology , RNA, Messenger/analysis , Rats , Rats, Inbred WKY , Reactive Oxygen Species/analysis , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Superoxide Dismutase/analysis , Transforming Growth Factor beta/analysis , Transforming Growth Factor beta/genetics , Ureteral Obstruction/pathology
3.
Pediatr Nephrol ; 15(3-4): 252-8, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11149121

ABSTRACT

The aim of this study was to examine the compromise of proximal tubule cells in steroid-resistant nephrotic syndrome patients with a histologic diagnosis of focal segmental glomerulosclerosis (FSGS) through assessment of the urinary levels of beta 2-microglobulin (beta 2M) and N-acetyl-beta-D-glucosaminidase (NAG) during active disease and remission over a follow-up period of 3 years. We studied 34 children with nephrotic syndrome: 12 with steroid-resistant nephrotic syndrome (SRNS) and massive proteinuria, 7 with steroid-dependent nephrotic syndrome (SDNS) and 15 with steroid-sensitive nephrotic syndrome (SSNS). Of the SSNS patients, 8 children were in remission (RM) and 7 were in relapse (RL). Seven healthy children were included as controls. Urinary beta 2M, measured by enzyme-linked immunosorbent assay, was significantly increased in the SRNS group as compared to the SDNS group (P < 0.01), SSNS in remission (P < 0.01), and controls (P < 0.01). There were no differences between the SRNS group and SSNS in relapse. Analysis of urinary N-acetyl-beta-D-glucosaminidase (U-NAG) by colorimetric assay showed significantly higher values in the SRNS group of patients than in SDNS, SSNS, and control groups. A positive correlation between U-NAG and proteinuria was demonstrated (r = 0.73, P < 0.01). The SRNS group of patients (n = 12, 11 with a histologic diagnosis of FSGS and one with diffuse mesangial proliferation) was treated with the same protocol of i.v. methylprednisone and oral cyclophosphamide. Long-term follow-up showed a progressive decrease in U-beta 2M and U-NAG excretion to control values in the 3rd year, except in one patient who did not respond to the treatment. In the FSGS patients, evaluation of the contribution of structural interstitial histological abnormalities, including each of the histological parameters considered in interstitial scarring to the functional tubule abnormalities assessed by beta 2M and NAG excretion, was performed by multiple regression analysis. The r2 values for beta 2M and NAG were 53.99%, P = 0.19, and 57.90%, P = 0.14, respectively; neither was significant. We conclude that: (1) proximal tubule cell dysfunction, partially affected by massive albuminuria, may account for the higher values of beta 2M and NAG excretion in the SRNS patients and (2) urine beta 2M and NAG levels are not helpful in identifying histological evidence of structural tubulointerstitial damage in children with steroid-resistant nephrotic syndrome.


Subject(s)
Acetylglucosaminidase/urine , Anti-Inflammatory Agents/therapeutic use , Kidney Tubules, Proximal/metabolism , Nephrotic Syndrome/drug therapy , Proteinuria/urine , Adolescent , Child , Child, Preschool , Drug Resistance , Enzymes/urine , Female , Follow-Up Studies , Humans , Infant , Kidney/pathology , Kidney Tubules, Proximal/enzymology , Male , Nephrotic Syndrome/urine , Recurrence , Steroids , beta 2-Microglobulin/urine
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