Experimental Research On The Treatment Of Autosomal Dominant Polycystic Kidney Disease Using PPARγ Agonists Combined With Amilorid

Objective:To evaluate the curative effect and safety of the treatment on male Han:SPRD rats with autosomal dominant polycystic kidney disease using PPARγagonists rosiglitazone combined with amilorid. And to research the side effect of rosiglitazone and the protection for myocardial of amilorid, and to analyze their potential mechaninsm on SD rats.Methods: Twenty Han:SPRD rats and forty SD rats were divided into four groups respectively: control group, rosiglitazone therapy group, amilorid therapy group and rosiglitazone combined with amilorid therapy group. All the rats were treated by daily gavage from 3 weeks after born to 6 month. Blood biochemistry detection were done every month to observe the blood electrolyte, urine electrolyte, BUN, creatinine, blood glucose and blood fat. Heart transonogram were used to observe the cardiac function of all the rats after gavaging 6 months. And all the rats were executed to obtain the heart, liver and nephros, they were weighed and sectioned for pathologic research. The fresh myocardium were used to observe the Na,K-ATPase activity on myocardial membrane, and to assese the effect of rosiglitazone and amilorid to Na,K-ATPase.Results: After administration of rosiglitazone combined with amilorid for 2 months, the rosiglitazone treatment groups and rosiglitazone combined with amilorid therapy group had less BUN,creatinine, Kidney weight/body weight, cyst index, fibrosis score and inflammatory cells infiltration compared with the control group by serological and histomorphometric analysis(P<0.05), while there was no significant difference between the former groups(P>0.05). And there was no significant difference of blood glucose and blood fat in the treatment groups compared with control group. The rosiglitazone treatment groups had higher body weight, heart weight/body weight, blood natrium and lower urine natrium compared with the control group, while there was no significant difference between therapeutic alliance groups and the latter, no matter Han:SPRD rats or SD rats. The cordis ultrasonograph showed that the rosiglitazoneby treatment group had dysfunction of LVPW:s, LVPW:d, IVS:d and IVS:s, what means the rosiglitazone displays some side effects such as fluid retention, which may lead to volume overload and aggravate the heart failure. While there was no difference of the EF and FS between the former and the control group. And the therapeutic alliance group had mild dysfunction of heart but no significant difference compared with control group. We observed myocardial tissue damage, edema and confused alignment of myocardial cell, lamellar necrosis, myofibrillolysis, myocardial fibers enlargement and wide myocardial cell space in rosiglitazone treatment group of two kinds of rats by histomorphometric analysis. While only a little change were found in the therapeutic alliance group, what may means amilorid mainly reversed the pathologic damage which relate to rosiglitazone. The rosiglitazone treatment group had lower Na,K-ATPase activity compared with control group(P<0.05), while Na,K-ATPase activity in the therapeutic alliance group was higher than the former(P<0.05).Conclusion: Rosiglitazone combined with amilorid therapy can retard the progression of male heterozygote(Cy/+) rats, significantly prolong the survival. But rosiglitazon displays some side effects such as fluid retention, which may lead to volume overload and aggravate the heart failure. And it may be owing to the Na,K-ATPase activity been inhibited by rosiglitazon. Amilorid can protect the Na,K-ATPase activity, and it can relief the side effect of heart relate to rosiglitazon when it combined with the latter to cure autosomal dominant polycystic kidney disease. Rosiglitazon combined with amilorid therapy is safety and effective for long term application, which shows well outlook for treatment of autosomal dominant polycystic kidney disease.