ABSTRACT
Tubulointerstitial fibrosis is the hallmark of diabetic nephropathy, which is the leading cause of end-stage renal disease worldwide. Roscovitine, an inhibitor of Cdks, exhibits anti-fibrosis effects. The present study was aimed to explore the protected role of roscovitine from renal fibrosis of diabetic nephropathy. In vivo study showed that roscovitine treatment significantly ameliorated renal functional and histological injuries in diabetic mice. It was also showed that roscovitine coordinately inhibited the expression of collagen, α-SMA, TGF-ß1, and retaining E-cadherin expression. At the cellular level, roscovitine treated HK2 cells cultured with high glucose. It was revealed that roscovitine successfully reduced α-SMA expression and ameliorated the decrease expression of E-cadherin, the two markers of tubular cell EMT. At the molecular level, roscovitine was found to exert this effect through inhibiting the up-regulation of TGF-ß1/p38MAPK pathway in high glucose cultured HK2 cells. These study demonstrated a novel mechanism that roscovitine has the anti-fibrosis effects by inhibiting the TGF-ß1/p38MAPK pathway in diabetic mice.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Diabetic Nephropathies/parasitology , Kidney/pathology , Roscovitine/therapeutic use , Transforming Growth Factor beta/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , Cell Line , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Dose-Response Relationship, Drug , Epithelial-Mesenchymal Transition/drug effects , Fibrosis , Humans , Kidney/drug effects , Kidney/metabolism , Kidney Function Tests , Male , Mice, Inbred Strains , Signal Transduction/drug effects , StreptozocinABSTRACT
OBJECTIVE: To determine whether pregnancy worsens renal function in women with diabetic nephropathy and the effect of pregnancy on diabetic retinopathy. DESIGN: Cross-sectional analytical study. PLACE AND DURATION OF STUDY: The study was conducted in OPD, Bahawal Victoria Hospital, Bahawalpur from September 1997 to June 2003. SUBJECTS AND METHODS: Thirty-five patients (aged 20-36 years ) identified with diabetic nephropathy and moderate to severe renal dysfunction(creatinine [Cr] > 1.4 mg/dl) at pregnancy onset by retrospective chart review. Alterations in glomerular filtration rate (GFR) were estimated. An equal number of non-pregnant premenopausal type I diabetic women with similar degrees of renal dysfunction served as controls for non-pregnant rate of decline of renal function and potential contributing factors. Student's t-test and repeated measures analysis of variance were analyzed. RESULTS: Mean serum Cr rose from 1.8 mg/dl prepregnancy to 2.5 mg/dl in the third trimester. Renal function was stable in 27%, showed transient worsening in pregnancy in 27%, and demonstrated a permanent decline in 45%. Proteinuria increased in pregnancy in 79%. Exacerbation of hypertension or pre-eclampsia occurred in 73% and 71% of these showed acceleration of disease during the pregnancy. All the patients had diabetic retinopathy, though proliferative retinopathy was diagnosed and treated in only 54.5.% prepregnancy. The retinopathy progressed, requiring laser therapy, in 45.4%. Macular edema was noted in 6 of the patients. Other diabetic complications included peripheral and autonomic neuropathy in 8 patients. CONCLUSION: Pregnancy induced progression is seen in the decline of renal functions. Patients with diabetic nephropathy were found to have a > 40% chance of accelerated progression of their disease as a result of pregnancy. Forty-five percent of the patients had permanent decline in GFR in association with pregnancy.
