Losartan slows down chronic progressive renal lesions in adriamycin-induced nephropathy

Abstract

Objective Studies in the last few years suggested that rennin-angiotensin system (RAS) might play an important role in renal progressive damage. RAS blockade could decrease protenuria and alleviate glomerulosclerosis and interstitial fibrosis, but the mechanism of which has been unclear. Therefore, adriamycin (ADR)-induced nephropathy rats were used as the animal model, the chronic progressive renal lesions of the model were studied for clinical manifestations, biochemical analyses of blood and urine, tissue pathologic lesions and molecular pathology in order to clarify the mechanism. Methods The experiments were performed on 72 male rats of 4 weeks old. The rats were randomly divided into three groups (nephropathy, treated and control groups). ADR (2 mg/kg) was intravenously administered twice at a 20-day interval. Treated group received the angiotensin Ⅱ type 1-specific receptor antagonist losartan [10 mg/(kg·d)] daily by gastric perfusion one week after the first injection of ADR until the end of the study. After 7 weeks, four rats in each group were sacrificed every 4 weeks for blood biochemical analyses and histological study. The final study was finished at week 27. Twenty-four hours urinary protein, and serum creatinine were checked with automatic biochemistry analyzer method. A semiquantitative score was used to evaluate the degree of glomerular and tubulointerstitium lesions. The expressions of TGF-β1 and collagen Ⅳ protein in renal tissues were measured with immunohistochemical method. The expressions of TGF-β1 and Ang mRNA in renal cortex were determined with reverse transcription polymerase chain reaction. Results (1)The ratio of kidney to body weight, 24 h urinary protein excretion and concentrations of serum creatinine in nephropathy rats were all higher than those in the treated rats and in the control rats at each time point during the experiment (P<0.01). (2)The glomerular sclerosis score was the highest in nephropathy rats and the lowest in the control rats, but the differences among them became significant only after 19 weeks(P<0.01); by 27 weeks of the experiment, the glomerular sclerosis scores were 29.03±4.64, 261.20±38.72 and 109.11±12.15 in control, nephropathy and treated groups, respectively. The score of tubulointerstitial pathologic lesions was more severe in nephropathy rats than that in the treated and the control rats(P<0.01), and more severe in the treated rats than that in the control rats at every time point after 7 weeks(P<0.01); at the 27 th week of the experiment, scores of tubulointerstitial pathologic lesions were 1.75±0.50, 13.0±1.41, 8.50±1.29 in control, nephropathy and treated groups, respectively. (3) The percentages of TGF-β1 and collagen Ⅳ staining positive-cells both in intraglomerular and tubulointerstitium in nephropathy rats were the highest after 11 weeks (P<0.01). (4)The expression of Ang mRNA in nephropathy rats was much higher than those in the treated and the control rats after 7 weeks(P<0.01), expression of Ang mRNA were 0.64±0.07, 1.43±0.06 and 1.07±0.1 in control, nephropathy and treated groups at week 27, respectively. The expression of TGF-β1 mRNA in nephropathy rats was up-regulated versus those in the treated and the control rats after 11 weeks (P<0.01). The expression of TGF-β1 mRNA were 0.71±0.07, 1.42±0.12, 0.94±0.09 in control, nephropathy and treated groups at week 27, respectively. Conclusion The persistent increase of renal RAS level could induce the generation of TGF-β1 in the kidney, which might be one of the important causes of in-reversible renal lesions. Losartan could contribute to retarding chronic progressive kidney damage, the effect could be mediated by decreasing the release of TGF-β1 in the kidney. Key words: Renin-angiotensin system; Losartan; Transforming growth factor beta; Nephrotic syndrome