| ObjectiveDiabetic kidney disease(DKD) in China has been rising rapidly. Renal tubule can be damaged early in DKD, which could result in fibrosis, predicting poor prognosis of renal function. Previous studies found that epithelial mesenchymal transition was closely related to renal tubular interstitial fibrosis, and Klotho, Wnt/beta-catenin and TGF-beta signaling pathway jointly participated in such process with elaborate cross talk. Therefore, it may be a way to inhibit renal EMT and tubular interstitial fibrosis by modulating these signaling pathways.In this research, paricalcitol was used for intervening DKD rats induced by streptozocin(STZ) to investigate the effect on renal tubular EMT and tubulointerstitial fibrosis.MethodsDKD rats model was achieved using STZ, and then rats were randomly divided into two groups:(1) Paricalcitol-intervened group(group P): DKD rats were injected intraperitoneally with paricalcitol dissloved in propylene glycol after the day when model was induced successfully in a dose of 0.4 μg.kg-1, 3/w.(2) DKD group(group D): DKD rats were given isopyknic propylene glycol. Normal group(group C) was also set in the research. Blood, urine and renal tissue samples were measured after 4 or 12 weeks with or without intervention of paricalcitol. Renal tissue was used for pathologic examination and the expression of E-cadherin, alpha-smooth muscle actin(α-SMA), fibronectin(FN), transforming growth factor-β1(TGF-β1), Wnt-4, β-catenin and klotho in kidney were measured using IHC and WB. In addition, the correlation among the indexes was analyzed.Results(1) Scr, BUN, 24 h urine protein and UACR increased sharply in group D in comparison with group C, while decreased significantly in group P in comparison with group D(P<0.05, for all).Compared with group C, serum P and i PTH increased, and Ca decreased in group D, while compared with group D, P and i PTH decreased, and Ca increased in group P(P<0.05, for all).(2) Histopathological changes were observed in group D, but relieved in group P compared with group C. Area of renal tubulointerstitial fibrosis increased in group D compared with group C, while decreased significantly in group P in comparison with group D(P<0.05, for all).(3) The protein level of E-cadherin decreased sharply, while α-SMA and FN increased significantly in group D compared with group C(P < 0.05, for all). Compared with D, the protein level of E-cadherin increased significantly, while α-SMA and FN decreased in group P(P < 0.05, for all).(4) The protein level of klotho decreased, while TGF-β1, Wnt-4 and β-catenin increased in group D compared with group C(P<0.05, for all). Compared with D, the protein level of klotho increased, while TGF-β1, Wnt-4 and β-catenin decreased in group P(P<0.05, for all).(5) The protein level of klotho had a significant negative correlation with fibrosis area, α-SMA, FN, TGF-β1, β-catenin and Wnt-4(r=-0.886, P<0.05; r=-0.806, P<0.05; r=-0.623, P<0.05; r=-0.749, P<0.05; r=-0.881, P<0.05; r=-0.855, P<0.05), while was positively correlated with Ecadherin(r=0.924, P<0.05).Conclusions(1) Paricalcitol can relieve renal tubular interstitial fibrosis, improve kidney dysfunction, and also reduce urine protein in DKD, indicating that paricalcitol can prevent diabetic kidney disease deterioration.(2) Paricalcitol can prevent renal tubular EMT in DKD.(3) Paricalcitol can increase the protein level of klotho, while inhibit the expression of TGF-β1, Wnt-4 and β-catenin in diabetic kidney disease. Increased klotho level, therefore inhibiting Wnt/beta-catenin signaling pathway and TGF-beta1 synthesis in kidney, may be one of the mechanisms that prevent renal tubular EMT and interstitial fibrosis in DKD. |
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