Research On Molecular Genetics And Early Prevention Of Diabetic Nephropathy

Research on Molecular Genetics and Early Prevention ofDiabetic NephropathyABSTRACTObjecfive:Diabetic nephropathy (DN) is one of the most serious complications of diabetes mellitus and the leading cause of end stage renal disease. There is an obvious genetic susceptibility of DN and early treatment is an effective method to delay the progression of DN. We design the study to explore the predisposing genes of DN and search for more effective method to prevent the progress of DN.Methods and Results:1.By restriction fragment length polymorphism(RFLP) analysis, we examined the association of DN with the polymorphism of heparan sulfate proteoglycan (HSPG) gene, receptor for advanced glycation end products (RAGE) gene and angiotensin-converting enzyme (ACE) gene. No significant differences were found in alleles and genotype frequencies of HSPG gene Banil-ll polymorphism as well as RAGE gene Gly82Ser polymorphism between normal and abnormal albuminuria in diabetic patients. Although the genotype frequencies of ACE gene insertion/deletion (l/D) polymorphism in normal albuminuria diabetics did not differ significantly from abnormal albuminuria diabetics, the alleles frequencies obviously differed between them. Also, DD genotype and D allele were more common in patients with abnormal albuminuria and less than 5 years duration of diabetes when compared with those with normal albuminuria and over 10 years duration of diabetes.2. We exMed the effect of HMG-CoA reductaSe nibitor (lovaschand sforastatin), ACE dribitor (cilaZaghl) and angiotensin II mpe lrecePtor Wonist (Ll58'809) on the eXPrssion of TGF-6l, IGF-l mRNAin cultUred human mesangial cells and concenLtrations of eXtracellularmatriX proteins in the suPematan. Lovastatin, simvastatin and cilaZaPrilcould effectively suPPress the excessive eXPression of TGF-6l and IGF-lM ofmesangial cells under high glucose concentfaton, and they coulda1so decrease the concentrations of TGF-0l, fibronectin, laminin and tyPeIV collagen in the suPematants. Combinations of cilaZaPri1 with lovastatinor simvastatin had more effective suPPression on the exPression of TGF-0lcomPared with each of them alone. Ll58,809 had the same effect ascilaZaPril on the SUppression of the excessive eXPression of TGF-6l, IGF-lmRNA in mesangial cells under high glucose conceniration and reducingthe conen of TGF-51, fibronectin, laminin and mpe IV collagen in thesuPematans. In addition, treamients with sAnvaStatin or/and cilaZaPril indiabetic rats sighficanly sUPPrssed TGF-01 mRN exPression in renalcortex and the coOPerative effect was observed in the combinaton grou.They could also reduce the accumlaton of TGF-0l, fibronectin, lamininand tyPe IV collagen in kidney Simvastain and cilaZaPril had the saxneeffect on the decreasing of urinny albUmin excreion, but after 8 weeksobservation, no more additional effect was found in decreasing the amounofalbuminuria in the combined treaAnent grouP.3. From the c1drical inVestigaton for the diabetc patents who hadaccePted the determination ofurinmp albo excretion in our hosPita, wefoUnd 57.2% of them had normoalbUminuria, 3 l .0% had microalfordriaand 11.8% had macroalbuminuria. That is to say 42.8% of them haddiabetc nePhropathy Logistic regression ana1ysis indicated that duration ofdiabetes, systolic blood pressure, LDL-C and APOB are the indePendentcorrelative factrs ofdiabetc nephropathy5Conclusion:l. There were no associaton of diabetic nePhroPathy wun HSPG geneBwt polymorphism and RAGE Gly82Ser polymorphism, so HSPG andRAGE gene were no the PredisPosing genes of diabetc nePhroPathyAlthough the genompe frequencies of ACE gene wer not associated withdiabetc nePhroPathy DD genompe and D al1ele of ACE gene migh be thepredictve factors for the early-onset diabetic nePhroPathy2. HMG-CoA reductaSe dribitor had the same effect as ACE iambitOron the suPPression of TGF-61 eXPression, the reducton of the accumulationof otelluar matrix Proti...