[The therapeutic effects of bosentan and valsartan on renal interstitial fibrosis of chronic aristolochic acid nephropathy].

OBJECTIVE

To investigate the therapeutic effects of endothelin receptor antagonist (bosentan) and angiotensin II type 1 receptor antagonist (valsartan) on renal interstitial fibrosis of rats with chronic aristolochic acid nephropathy (CAAN).

METHODS

A rat model of CAAN was established by gavage with extract of Aristolochia manshuriensis Kom intermittently, and then they were divided into the following three groups, i.e. model group, bosentan group (100 mg.kg(-1).d(-1) by gavage) and valsartan group (30 mg .kg(-1).d(-1) by gavage). Control group (CTR) only received tap water by gavage. Each group consisted of 6 rats. At the end of 1st, 4 th, 8 th, 12 th and 16 th week, urinary protein excretion, urinary beta2 microglobulin (beta2-mG) and serum creatinine (SCr) were measured. Afterwards the rats were sacrificed. The relative area of renal interstitial fibrosis on pathological section was semi-quantitatively determined. The mRNA and the protein expression of transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF), plasminogen activator inhibitor-1 (PAI-1), tissue inhibitor of metalloproteinase-1 (TIMP-1) and collagen I (ColI) in kidney tissue was semi-quantitatively determined with reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemical staining, respectively.

RESULTS

Compared with CTR, urinary protein excretion, urinary beta2-mG and Scr were significantly increased (P < 0.05 or 0.01) and relative area of interstitial fibrosis was also significantly enlarged in the model group (3.964 +/- 0.739%, CTR 0.158 +/- 0.059%, P < 0.01). Compared with CTR, the expression of TGF-beta1, CTGF, PAI-1, TIMP-1 and Col I mRNA and protein was significantly up-regulated in the model group (P < 0.01). After intervention with bosentan or valsartan the up-regulating above mentioned parameters were all significantly inhibited (P < 0.05 or 0.01). However, there was no difference between bosentan group and valsartan group.

CONCLUSIONS

Bosentan and valsartan both can ameliorate renal interstitial fibrosis and improve renal function in rats with CAAN. These responses may result from the inhibition effects on the promoting factors of ECM synthesis (TGF-beta1, CTGF) and the antagonistic factors of ECM degradation (PAI-1, TIMP-1).