ABSTRACT
The role of endoplasmic reticulum (ER) stress in kidney diseases is not well elucidated. Fifty patients with primary glomerular diseases (PGD): minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous glomerulonephritis (MGN), membranoproliferative glomerulonephritis (MPGN), and crescentic glomerulonephritis, n = 10 (each group) were enrolled. MCD, FSGS, and MGN patients were sub-grouped as nonproliferative glomerulonephritis (NPGN) and MPGN, RPGN as proliferative glomerulonephritis (PGN). Glucose regulated proteins (GRP-78), growth arrest and DNA damage inducible proteins (GADD-153), and Bcl-2 protein expression was analyzed by Western blotting, immunofluorescence and immunohistochemistry in the kidney biopsy. Up regulation of GADD-153, GRP-78, with more pronounced expression in PGN vs. NPGN (P < 0.05) and down regulation of Bcl-2 proteins was observed in the GN (PGD excluding MCD) as compared to MCD (P < 0.05). Our results suggest that renal injury in PGD is associated with ER stress and ER stress may be involved in the rapid progression of PGN to renal failure.
Subject(s)
Endoplasmic Reticulum/pathology , Gene Expression Regulation , Glomerulonephritis/metabolism , Heat-Shock Proteins/genetics , Proto-Oncogene Proteins c-bcl-2/genetics , Transcription Factor CHOP/genetics , Adolescent , Adult , Disease Progression , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum Chaperone BiP , Female , Glomerulonephritis/classification , Glomerulonephritis/genetics , Glomerulonephritis, Membranoproliferative , Glomerulonephritis, Membranous , Glomerulosclerosis, Focal Segmental , Heat-Shock Proteins/analysis , Humans , Kidney Glomerulus/chemistry , Kidney Glomerulus/metabolism , Kidney Glomerulus/pathology , Male , Proto-Oncogene Proteins c-bcl-2/analysis , Renal Insufficiency/etiology , Transcription Factor CHOP/analysis , Young AdultABSTRACT
OBJECTIVE: To evaluate the status of oxidative stress in patients with different primary glomerular diseases (PGD) which have differential predisposition to renal failure. METHODS: Seventy-three patients with PGD and 50 controls were enrolled in the study. They were sub-grouped into non-proliferative glomerulonephritis (NPGN) and proliferative glomerulonephritis (PGN). Levels of serum malondialdehyde (MDA), reactive nitrogen intermediates (RNI), plasma total homocysteine (tHcy), urine 8-isoprostane (8-IP), RBC thiols, glutathione-S-transferase (GST) and serum superoxide dismutase (SOD) were measured spectrophotometrically. RESULTS: PGD patients showed a significant increase in MDA, RNI, tHcy, 8-IP levels (P < 0.05) and decreased SOD, total thiols and protein bound thiol levels as compared to controls (P < 0.05). Significantly higher levels of tHcy, MDA and 8-IP (P < 0.05) and lower SOD enzyme activity (P < 0.05) were observed in PGN group as compared to NPGN and control groups. These changes remained significant even after adjustment was made for creatinine. CONCLUSIONS: Oxidative stress in PGN is significantly higher than NPGN, indicating higher oxidative stress in these patients, independent of degree of renal dysfunction.
Subject(s)
Kidney Diseases/metabolism , Kidney Glomerulus , Oxidative Stress , Adolescent , Adult , Animals , Dinoprost/analogs & derivatives , Dinoprost/blood , Glomerulonephritis/metabolism , Glomerulonephritis/physiopathology , Homocysteine/blood , Humans , Kidney Diseases/physiopathology , Kidney Glomerulus/metabolism , Kidney Glomerulus/pathology , Malondialdehyde/blood , Middle Aged , Reactive Nitrogen Species/bloodABSTRACT
The goals of our present study were to measure plasma homocysteine levels and determine their association with methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms (C677T and A1298C) in essential hypertensive subjects. Plasma total homocysteine and folic acid levels were measured in essential hypertensive patients (n = 153) before and after oral supplementation with either 5 mg folic acid tablet/day or 5 mg placebo/day for 4 weeks and compared with age and sex matched normotensive controls (n = 133). MTHFR gene polymorphisms (C677T and A1298C) were studied by restriction fragment length polymorphism and correlated with plasma homocysteine levels. Homocysteine levels were significantly higher in hypertensive patients as compared to controls and showed a negative correlation with plasma folate levels. Folic acid supplementation (5 mg/day) for 4 weeks resulted in a significant decrease in plasma homocysteine concentrations in these patients. Patients carrying MTHFR 677T allele (OR = 1.90; 95%CI: 1.14-3.19) or MTHFR 1298C (OR = 2.6, 95%CI: 1.55-4.40) allele were at increased risk of hypertension. The frequency of co-occurrence of MTHFR 677 CT/1298 CC genotypes was significantly higher in the patients compared to controls (P < 0.05) and was associated with increased risk of hypertension (OR = 3.54, 95%CI: 0.37-4.30). Subjects with MTHFR 1298 CC genotype had significantly higher homocysteine levels compared to those with MTHFR 1298 AA genotype (P < 0.05). Our results indicate that MTHFR 677T and 1298C alleles and co-occurrence of MTHFR 677 CT/MTHFR 1298 CC genotypes are associated with increased risk of hypertension and MTHFR 1298 CC genotype is associated with higher homocysteine levels in our subjects.
