OBJECTIVETo investigate the trend and potential pathogenic role of nuclear factor (NF)-kappaB P(65)/Rel-A mRNA and angiotensin-II (AngII) receptor type 1 (AT(1)) proteins expression, and the relativity between them in early stage of renal tubulointerstitial lesions in young rats with adriamycin nephrosis and the interfering effects of treatment with angiotensin converting enzyme inhibitor (ACEI) benazepril and ACEI combined with AngII type 1 receptor antagonist (AT(1)RA) Losartan.

METHODSMale young Wistar rats with adriamycin nephrosis were used as experimental models. At different time points (weeks 1, 2, and 3 in early nephritic phase, the urinary protein and blood biochemical parameters were measured, and P(65)/Rel-A mRNA was detected; AT(1) protein expression was determined by in situ hybridization and immunohistochemical methods. The relativity between them was evaluated.

RESULTSIn the early phase of tubulointerstitial lesions, following adriamycin injection and proteinuria aggravated progressively, at week 3, the proteinuria level had reached heavy proteinuria (123.2 +/- 7.7 mg/24 h). The serum parameters reflecting renal function were elevated. The inflammatory cells infiltrated into renal tissues, especially in tubulointerstitial regions, were increased markedly. Swelling of tubular epithelial cells, broadened tubulointerstitial areas, and protein casts in tubule were observed. In situ hybridization and immunochemical staining showed that AT(1) protein was expressed in tubular epithelial cell cytoplasm and on nuclear membranes (AT(1): 1st week 19.8 +/- 1.1%, 2nd week 25.0 +/- 2.6%, 3rd week 37.1 +/- 1.0% (control: 10.3 +/- 0.8%, 10.4 +/- 1.6%, 10.2 +/- 1.5%); and P(65)/Rel-A mRNA expression in the same locations was upregulated. P(65)/Rel-A translocation from cytoplasm into nucleus increased markedly simultaneously. The positive signal of hybridization dominated in cytoplasm gradually became dominant in the nuclei as the pathological changes progressed. The semiquantitative expression of P(65)/Rel-A was 24.0 +/- 3.3% at week 1, 34.2 +/- 2.4% at week 2, 39.9 +/- 6.4% at week 3, while the values of controls were 8.5 +/- 0.4%, 8.7 +/- 1.0%, and 8.4 +/- 0.9%, respectively. There was a positive correlation between AT(1) and P(65)/Rel-A expression in localization and time phase (r = 0.857, P < 0.01). However, the tendency of those factor's expression was all decreased in each treated group, the semiquantitative results were AT(1): 14.6 +/- 2.1%, 13.7 +/- 2.3%, 11.4 +/- 1.1%; P(65)/Rel-A: 18.5 +/- 3.4%, 22.8 +/- 1.6%, 26.7 +/- 4.9% at 1, 2, 3 weeks in ACEI treated group; AT(1): 12.4 +/- 1.5%, 11.1 +/- 1.0%, 10.3 +/- 0.8%; P(65)/Rel-A: 17.9 +/- 5.0%, 21.3 +/- 6.0%, 22.5 +/- 2.5% in AT(1)RA (Losartan) group, respectively. The significant difference were observed between all groups in different time points (P < 0.05).

CONCLUSIONSThe present study suggested that NF-kappaB (P(65)/Rel-A) mRNA expression and its activity was enhanced significantly that synchronized with aggravating injures in tubulointerstitial lesions initial period induced by proteinuria-loading in nephrotic young rats. This tendency was related with AngII and its receptors system that may accelerate lesions progressing in many renal diseases.