Expression Of Hepatocyte Growth Factor In The Renal Interstitial Fibrosis Of Obstructive Nephropathy In Rats And The Regulation Of Losartan

Objective:Tubulointerstitial fibrosis is often recognized as an endpoint outcome of a wide range of chronic renal disease, regardless of underlying pathogenesis. Studies show that deterioration of renal function is largely determined by the extent of tubulointerstitial alterations in many forms of renal disease both in experimented animal models and in patients. We pay more and more attention to the onset and the progression,as well as prevention and therapy.Studies on all kinds of growth factors are popular.Hepatocyte growth factor is one of the anti-fibrogenic growth factor,which plays a role in protecting the liver and lungs from liver cirrhosis and lungs fibrosis.In tubulointerstitial regions,HGF is expressed in interstitial cells,presumably epithelia cells and macrophages, HGF seems to act on those cells through autocrine-or paracrine-related pathways. As a negative regulator to renal fibrosis,HGF ameliorates renal fibosis through promoting proliferation,inhibiting apoptotic,activating matrix degradation, suppressing myofibroblast activation,regulating proteoglycan synthesis.Studies on several models of chronic renal disease including ICGN, UUO, remnant kidney and chronic allograftenephropathy show endogenous renal HGF levels decrease along with the progression of renal fibrosis and lower than that in nomal kidney at advanced stages of the disease.Thus the renal HGF level correlates with a decrease in tubular proliferation and inversely correlates with a increase in the renal TGF- P i level,ECM accumulation and tubular apoptosis.Neutralization of endogenous HGF strongly accelerated progression of renal fibrosis and dysfunction, TGF- P i expression and ECM accumulation were increased concomitantly with increases intubular apoptosis and with decrease in tubular proliferation. In cotrast the administration of HGF strongly suppressed TGF- 3 i expression and prevented the onset of renal fibrosis and chronic renal failure.Those findings mean that the reciprocal balance between TGF- 3 i and HGF has a determinant role in the pathogenesis and theraputics of a variety of fibrosis-related disease. The onset of renal fibosis is not only associated with the increase of TGF- 3 ( but also with the decrese of HGF. Like other growth factor,HGF is also in the whole growth factor net and regulated by others. TGF- 3 i and Ang II are its negative regulators. Ang II receptor blocker has protective action to kidney,but it is unknown whether it can regulator the expression of HGF. Our studies aim to find one of the mechismes how Ang II receptor blocker protects kidney. Is it through blocking Ang II and making HGF increased? Rat UUO models was used in our studies. We administed Losartan to UUO rats. Through HE stain ^ routine immunohistochemical, > RT-PCR method, weresearched the changes of expression of HGFmRNA> protein and TGF- 3 i protein. We hope our studies can make the actions of HGF and Ang II receptor blocker clearer.Methods: 60 male SD rats were randomly divided into 3 groups: sham-operated group (A^ UUO group (B)> UUO with Losartan treated group (C), (n=20).Each group was also randomly divided into 3 ^ 6> 9n 14 groups in term of the days after surgery (n=5). Under pentobarbitale sodium anesthesia, the rats left ureter was ligated with 0 silk at two points and cut between the ligatures. Then the unilateral ureteral obstructive rat model was established. Sham-operated rats had their ureters manipulated but not ligated. Losartan began to administed 2 days before surgery. Rats were killed after 3 ^ 6^ 9> 14 days. In obstructed kidney, HGF mRNA was detected by RT-PCR. At the same time, the changes of HGF and TGF- f3 i protein were analyzed by routine immunohistochemical method. Use HE stain to examine the area of pathological changes.Results: There were different degrees of interstitial fibrosis tubular basement membrane thicking tubular dilation,epithelial cell necrosis and the interstitial lesion area expansion in the obstructed kidneys of group B3 ^ 6 > 9 n 14days after UUO.The lesion area of the renal interstitial was significantly increased in the obstructed kidneys compared with that of group A. However, the lesion area in kidneys of group C significantly decreased compared with that of group B.(P<0.01) In group B,the expression of HGF mRNA and protein were higher than normal...