Influence of retinoic acid receptor-mediated all-trans retinoic acid on renal tissue cell proliferation and apoptosis in rats with diabetic nephropathy / 中华肾脏病杂志

ABSTRACT

Objective To investigate the influence of retinoic acid receptor (RAR-α,RAR-β and RAR-γ)-mediated all-trans retinoic acid (ATRA) on renal tissue cell proliferation and apoptosis in rats with diabetic nephropathy,and to analysze the possible mechanism. Methods Male SD rats were randomly divided into normal control group (group N,n=10) and diabetic model group (n=20).Diabetes was induced by streptozotocin(STZ) injection.After successful modeling,the model rats were randomly divided into diabetes group (group D,n=10) and ATRA treatment group (group T,n=10).Rats in group T received ATRA 10 mg·kg-1·d-1 by gavage from the 2nd day of successful modeling for 8 or 12 weeks,meanwhile group N and group D received same volume distilled water.In each group,5 rats were sacrificed respectively at the 8th week or the 12th week,then biochemical markers were measured and kidney pathology was examined.Apoptosis index(AI)of renal tissue cells of each group was tested by TUNEL.The expressions of RAR-α,RAR-β and RAR-γ in renal tissues were tested using indirect immunofluorescence.The expressions of type Ⅰ collagen and laminin as proliferation indicators,along with Smac and caspase-3 as the correlated factors of apoptosis in renal tissue of each group were tested by immunohistochemistry staining.The mRNA expressions of Smac and caspase-3 were tested using real-time fluorescence quantitative PCR. Results Compared with group N,24 h urine protein,serum creatinine,blood urea nitrogen,ratio of kidney weight/body weight increased significantly (P＜0.05,respectively) in group D,and further increased with observation time.Compared with the group D,24 h urine protein and ratio of kidney weight/body weight decreased in group T (P＜0.05,respectively).Compared with group D,the group T presented minor pathological changes.TUNEL assay indicated that compared with group N,the group D showed an obvious increase in renal cell apoptosis in time-dependent manner,and the group T showed a decrease compared with the group D (P＜0.01,respectively).Compared with group N,the expression of RAR-α and RAR-β positive cells number in group D were decreased (P＜0.01,respectively).Compared with group D,the expression of RAR-α and BAR-β positive cells number in group T increased (P＜0.01,respectively).Renal tissues of each group did not show expressions of RAR-γ.After 12 weeks,compared with group N,expressions of type-Ⅰ collagen,laminin,Smac and caspase-3 protein in the glomerular mesangial area and basement membrane of renal tissues in group D increased significantly (P＜0.01,respectively),and enhanced with time.Compared with the group D,expressions of type Ⅰ collagen,laminin,Smac and caspase-3 protein in group T decreased (P＜0.01,respectively).Compared with the group N,group D had an obvious increase in the mRNA expressions of Smac and caspase-3,and a significantly decrease in group T (P＜0.01,respectively). Conclusions ATRA may prevent the cell proliferation and apoptosis in diabetic renal tissue through its receptor-mediated pathway,and may protect rats against diabetic nephropathy.