Effect Of Telmisartan And Cordyceps Sinensis On Renal Tubular Epithelial-Mesenchymal-Transitionin In Diabetic Nephropathy Rats

As the incidence of diabetes (DM) increased in recent years, it has become a global health burden.Diabetic nephropathy (DN) is one of the most common and severe microvascular complications of thediabetes, and its basic pathological change is extracellular matrix (ECM) reconstruction, which lead toglomerulosclerosis and renal interstitial fibrosis. EMT is now recognized as a key contributor to the loss ofrenal function throughout the nephron in diabetic nephropathy. The formation of α-smooth muscle actin(α-SMA) is a critical step in the EMT process, suggesting the extent of EMT. Studies have shown thattransforming growth factor-β (TGF-β) is the most effective factor in vitro caused the EMT. Bonemorphogenetic protein-7(BMP-7) belongs to the TGF-β superfamily, mainly expressed in tubular epithelialand the podocytes tubule cell, when the cells are injured, the expression of BMP-7is decreased. Throughexogenous BMP-7to protect kidney function now is considered as one of the most important factor toreversal renal fibrosis. Angiotensin II receptor antagonists (ARB) has been used clinically, primarilythrough its hemodynamic protection, but the mechanism of inhibition of renal interstitial fibrosis is notclear. Cordyceps sinensis as an important agents for renal protection mechanism is more complicated andconfusing. We will observe the expression of α-SMA、BMP-7and TGF-β in renal tissue of diabeticnephropathy rat model, as well as the change of the three indexes after the treatment of telmisartan andCordyceps, in order to find the effect to renal tubular epithelial to mesenchymal transdifferentiation and themechanism of telmisartan Cordyceps sinensis for protecting kidneys.Objective: To observe the expression of α-SMA、BMP-7and TGF-β in renal tissue of diabeticnephropathy rat model, as well as the change of the three indexes after the treatment of telmisartan andCordyceps, in order to find the effct of EMT in the development of DN and the mesenchymaltransdifferentiation and the mechanism of telmisartan Cordyceps sinensis for protecting kidneys.Methods: We established the diabetic nephropathy rat modle by single intraperitoneal injection ofstreptozotocin (STZ). Then randomly divided the DN model rats into four groups: non-treatment DN modelgroup (n=9), telmisartan-treated group (n=9), Cordyceps sinensis treated group (n=9),combination-treated group (n=10). In addition, we selected10normal rats served as control group. Thetelmisartan-treated group rats were gavaged once a day with telmisartan (8mg/kg of body weight). The Cordyceps sinensis-treated group rats were gavaged with Cordyceps sinensis(2.5g/kg of body weight) oncea day. The combination-treated group rats were gavaged with the two drugs once a day. The other twogroups were gavaged with drinking water everyday. The test time lasted for eight weeks, then determinatedthe urine of24hours, the volume of urinary protein and renal function markers. Then observed theexpreesion ofα-SMA、BMP-7and TGF-β by immunohistochemistry ABC method.Results:(1) The treatment groups rats, including one drug separately and two drugs combination,compare with DN model group rats, the kidney function (both BUN and Cr) is significantly decreased (P<0.01); but increased to normal group.(2) Compared with normal control group rats, the24hours urinaryprotein quality of the DN model group rats were significantly increased (P <0.01), after the treatment oftelmisartan and Cordyceps sinensis separately and both two drugs combination, the24hours urinaryprotein quality significantly decreased (P <0.01).(3) Inflammatory cells infiltration, tubular vacuolizationand tubulointerstitial fibrosis could be seen in DN group, and its index of renal tubular-interstitial injuryelevated significantly （P<0.01）when it was compared with normal group. Renal tubular-interstitial injuryin other three treatment groups significantly released（P<0.01）.(4) The expression of both α-SMA andTGF-β were significantly suppressed among subjects in DN group（P<0.01）, but the expression of BMP-7were contrast decreased (P <0.01). In other three treatment groups, the expression of both α-SMA andTGF-β were significantly reduced and the expression of BMP-7was increased compare with DN group (P<0.01).(5) α-SMA and TGF-β were positively correlated with urinary protein quality and renal functionmarkers significantly (P <0.01); but BMP-7was negatively correlated with them (P <0.01); α-SMA waspositively correlated with TGF-β(P <0.01), BMP-7was negatively correlated with both α-SMA and TGF-βsignificantly (P <0.01).Conclusions:1. The increased of expression of α-SMA in DN rats suggestted that there is EMT in DN rats.2. The expression of α-SMA is concerned with TGF-β significantly, suggesting that TGF-β caninduce the expression of α-SMA, and promote the occurrence of EMT3. The expression of BMP-7was significantly negatively correlated with α-SMA and TGF-β,suggesting that BMP-7maybe can through inhibition of TGF-β expression to inhibite the progressof the EMT 4. Telmisartan and Cordyceps sinensis can slow down the process of renal fibrosis decreasing ECMand impeding EMT, and the effect is better if they joint application.