Molecular Phenotype Of Epithelial Mesenchymal Transition And Treatment In Young Rats With Chronic Renal Failure

Objective To investigate the tide of transforming growth factor-β1 (TGF-β1) expression in chronic progressive renal tubulointerstitial lesions of 5/6 nephrectomized remnant kidney young rats, and the tide of E-cadherin, fibroblast-specific protein -1 (FSP-1),α-smooth muscle actin (α-SMA) and vimentin in the course of tubular epithelial-mesenchymal transdifferentiation (EMT) mediated by TGF-β1, and to evaluate interfering effects of angiotensin converting enzyme inhibitor (ACEI) combined with angiotensin receptor blockade (ARB).Methods Ninety-six young female 3~4 week-old SD rats were randomized into sham operation group (n=32), 5/6NX untreated group (n=32) and 5/6NX treated group (treated with ACEI and ARB, n=32). Five-sixth nephrectomized remnant kidney young rats serviced as a chronic renal failure model. After finishing the operation, we detected the renal function and pathology so as to evaluate whether the models were successfully established. Rats in 5/6NX treated group were received daily intragastric administration of ACEI and ARB after establishing the models successfully. Eight rats of each group were randomly selected respectively at week 2, 4, 8 and 12. Serum creatinine and blood urea nitrogen were detected, then we killed the rats and took out of the kidney. HE staining was employed to observe renal histological changes. The protein expressions of TGF-β1, E-cadherin, FSP-1,α-SMA and vimentin in renal tubular epithelial cells were assessed by immunohistochemistry.Results⑴HE staining. In sham operation group, there were no evident changes. In 5/6NX untreated group, the tubulointerstitial lesions progressively developed the fibrosis following the experimental time, with infiltrating of inflammatory cells in tissues, swelling of tubular epithelial cells, collapsing of renal tubules and widening of renal tubules space. In 5/6NX treated group, the tubulointerstitial lesions were relatively ameliorated.⑵Immunohistochemical staining. The expression of E-cadherin was gradually decreased in 5/6NX untreated group and 5/6NX treated group with the experimental time prolonging. Compared with sham operation group, there was significant difference at different time points(P<0.05), and there was significant difference between 5/6NX untreated group and 5/6NX treated group at week 8 and 12(P<0.05).The expressions of FSP-1 and vimentin were gradually increased in 5/6NX untreated group and 5/6NX treated group. Compared with sham operation group, there was significant difference at different time points(P<0.05), and there was significant difference between 5/6NX untreated group and 5/6NX treated group at week 4, 8 and 12(P<0.05).The expression ofα-SMA was gradually increased in 5/6NX untreated group and 5/6NX treated group. Compared with sham operation group, there was significant difference at week 4, 8, 12 (P<0.05), and there was significant difference between 5/6NX untreated group and 5/6NX treated group at week 4, 8 and 12(P<0.05). The expression of TGF-β1 was gradually increased in 5/6NX untreated group and 5/6NX treated group. Compared with sham operation group, there was significant difference at week 4, 8, 12(P<0.05), and there was significant difference between 5/6NX untreated group and 5/6NX treated group at week 4, 8 and 12(P<0.05).Conclusion During the process of chronic progressive renal tubulointerstitial lesions of remnant kidney 5/6 nephrectomized young rats, the up-regulation of TGF-β1, which mediated tubular epithelial-mesenchymal transdifferentiation (EMT), was implicated in the down-regulation of E-cadherin, along with the up-regulation of FSP-1,α-SMA and vimentin. Administration of angiotensin converting enzyme inhibitor (ACEI) combined with angiotensin receptor blockade (ARB) could reverse the expressive tide.