Fluorofenidone Reverses Renal Interstitial Fibrosis In Unilateral Ureteral Obstruction Rats

Background:Chronic kidney disease(CKD) has become an increasingly burdensome health problem, with high costs to the healthcare system. Once end-stage renal disease (ESRD) occurs, patients need access to maintenance hemodialysis treatment or kidney transplantation to prolong life. New therapeutic strategies should be targeted at developing effective methods for inhibiting renal interstitial fibrosis. To explore effective anti-fibrotic therapy to slow the progression of chronic kidney disease holds great promise.Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are widely used in clinical treatment, they can reduce the blood pressure, as well as reduce proteinuria, thereby slowing the progression of renal disease. Fluorfenidone (AKF-PD) is a brand new pyridone agent synthesized by our study group, and it has potential broad-spectrum antifibrotic characteristics. The preliminary experiments have demonstrated its low toxicity and anti-fibrotic functions in renal interstitial fibrosis. Our recent results showed that it significantly reduced epithelial-mesenchymal transdifferentiation and the proliferation of renal fibroblasts. In addition, AKF-PD significantly reduced interstitial matrix deposition to reverse renal interstitial fibrosis. Our preliminary experiments have confirmed that AKF-PD has better anti-fibrotic effect than enalapril (ACEIs).This study aims to compare the effect of AKF-PD on reversing renal interstitial fibrosis in Unilateral Ureteral Obstruction Rats to that of Losartan (ARB).Objectives:To investigate the antifibrotic effects of AKF-PD and Losartan in renal tissue of UUO model rats.Methods:20 male SD rats were randomly divided into 4 groups with 5 animals in each group:Sham operated group (N), UUO model group (M), AKF-PD(A) and Losartan(L) treated groups. The rats in UUO model group and two treated groups underwent UUO operation.14 days after the operation, all rats were sacrificed. Tissue from the obstructed kidneys was collected for HE and Masson staining, as well as for immuno-histochemical staining to detect the expression of type I and III collagen proteins.Results:1. HE staining tubulointerstitial damage index: Fourteen days after obstruction, The UUO model group's score was higher than the sham operation group (P<0.05); AKF-PD and Losartan treated groups had scores significantly lower than the model group (P<0.05); whilst there was no difference between the two treated groups(P>0.05).2. MASSON staining for the semi-quantitative determination of collagen areas:The model group showed significantly higher expression than the sham operation group (P<0.05); Compared with the model group, the collagen areas of AKF-PD and Losartan treated groups were decreased (P<0.05); The collagen areas of the AKF-PD treated group were smaller than that of the Losartan treated group(P<0.05).3. Immunohistochemistry results:Compared with the sham operation group, the contents of collagenâ… and collagenâ…¢in the model group increased significantly(P< 0.05); Collagenâ… and collagenâ…¢production were decreased by AKF-PD (P<0.05) and Losartan (P<0.05); The collagenâ…¢content was much lower in the AKF-PD group than the Losartan treated group (P<0.05).Conclusion:1. Treatment with either AKF-PD or Losartan improved the pathological changes in UUO renal tissue, and significantly reduced collagen deposition in the renal interstitium.2. AKF-PD has better antifibrotic effect than Losartan, especially as regards decrease in collagen deposition and collagenâ…¢expression.