Effect of all-trans retinoic acid on renal expressions of matrix metalloproteinase-2, matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in rats with glomerulosclerosis

Abstract

In kidney injury the accumulation of extracellular matrix (ECM) plays an important role and precedes the development of glomerulosclerosis (GS). There is great interest in agents that may interfere with such accumulation of ECM. Therefore, a rat model of GS was established to investigate the effect of all-trans retinoic acid (ATRA) on the renal expressions of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1). Eighty Wistar rats were randomly divided into four groups: sham operation group (SHO), GS model group without treatment (GS), GS model group treated with benazepril (GB) and GS model group treated with ATRA (GA), n = 20, respectively. The disease was established in the GS rats by uninephrectomy and adriamycin (5 mg/kg) injection through the tail vein. Serum creatinine (Scr), blood urea nitrogen (BUN) and urine protein (Upro) were measured. Renal abnormality was evaluated at the end of 12 weeks. Immunohistochemical analysis was performed on renal tissue to detect the expression of collagen IV (Col-IV), fibronectin (FN), MMP-2, MMP-9 and TIMP-1 protein. MMP-2 and MMP-9 activity was detected by gelatin zymography. Real-time reverse transcription polymerase chain reaction (real-time RT-PCR) was used to detect the expression of MMP-2, MMP-9, and TIMP-1 mRNA. In comparison with group GS, group GA and group GB exhibited levels of BUN and 24 h urinary protein and a glomerulosclerosis index (GSI) that were significantly reduced (P < 0.05); the level of Scr in group GA was reduced too (P < 0.05). ATRA and benazepril also significantly down-regulated Col-IV, FN expression and TIMP-1 expression (protein and mRNA) (P < 0.05). In contrast, the expressions of MMP-2, MMP-9 mRNA and protein, and activity in groups GA and GB were enhanced (P < 0.05). However, there were no significant differences in MMP-2, MMP-9 mRNA and protein expression, or activity, between the ATRA and GB groups (P > 0.05). In conclusion, ATRA may protect renal function and step down the progression of GS by reducing the expression of TIMP-1, enhancing the expression and activity of MMP-2 and MMP-9, and regulating the ratio of MMPs/TIMPs to dynamic balance, so as to reduce the accumulation of ECM.

Paradoxical expressions of natriuretic peptide receptor-C and neutral endopeptidase account for C-type natriuretic peptide decline during the progression of experimental obstructive nephropathy

“…The sequences of oligonucleotides and sizes of PCR products were, for CNP, sense: 5'-AACATCCCAGACCGCTCATG-3', antisense: 5'-CAA GAA GGG CTT GTC CAA AGG-3'(73 bp) 9 for NPR-B, sense: 5'-AAC GGG CGC ATT GTG TAT ATC TGC GGC-3', antisense: 5'-TTA TCA CAG GAT GGG TCG TCC AAG TCA-3' (692 bp) 10 for NPR-C, sense: 5'-ATA GTG CGC TAC ATC CAG GGC AGT-3', antisense: 5'-TCC AAA GTA ATC ACC AAT GAC CTC CTG GGT ACC TGC-3' (573 bp) 10 for NEP, sense: 5'-CCC CGC CGG CAT TT-3', antisense: 5'-GCC CCC ATA GTT CAA TGA GTT G-3' (66 bp) 11 for glyceraldehyde-3-phosphate dehydrogenase (GAPDH), sense: 5'-TGT GAG GGA GAT GCT CAG TG-3', antisense: 5'-GGC ATT GCT CTC AAT GAC AA-3' (229 bp). 12 One microgram total RNA from the renal tissue of each rat was reverse transcribed into cDNA with an ExScript RT reagent kit (Takara Biotechnology Co. Ltd, Dalian, China). CNP, NPR-B, NPR-C and NEP were amplified with SYBR Premix Ex Taq (Takara Biotechnology Co. Ltd).…”

Association of all-trans retinoic acid treatment with the renin-angiotensin aldosterone system expression in glomerulosclerosis rats

“…In our previous study, we found that ATRA could achieve a similar effect to a RAAS inhibitor (benazepril) to prevent the progression of GS lesions in GS rats. 9,10 However, whether the ATRA treatment was associated with the expression of RAAS in GS rats was not elucidated. This study was performed to investigate the association of ATRA treatment with RAAS expression.…”

Expression of MMP-2 and TIMP-1 in Renal Tissue of Patients with Chronic Active Antibody-mediated Renal Graft Rejection

“…Wagrowska- Danilewicz et al [8] found that the expression of both MMP-2 and TIMP-1 were upregulated in reanal allografts of 17 chronic allograft nephropathy patients compared to renal tissue of 11 normal controls, which suggest the remodeling of impaired renal structure have correlation with the regulation imbalance of MMP-2 and TIMP-1. The expression of TIMP-1 was downregulated, while the mRNA and protein expression and activities of MMP-2 and MMP-9 were enhanced after treatment with benazapril and all-trans retinoic acid (ATRA) in Wistar rat model of glomerular sclerosis compared to normal group [9]. The results of above studies suggest the ATRA exerts protection role by downregulate the expression of TIMP-1 and upregulate the mRNA expression and activity of MMP-2 and MMP-9, regulate the balance of the ratio of MMPs and TIMPs, and thus decrease ECM sediment.…”