| Chronic Renal Failure (CRF) is a clinical syndrome associated with fluid, electrolyte, and hormone imbalances and metabolic abnormalities, which is a progressive loss of renal function over a period of months or years. There is no specific treatment unequivocally shown to slow the worsening of chronic kidney disease. The number of patients with end-stage renal disease (ESRD) has increased rapidly over the last three decades, and prior to the advent of renal replacement therapy (dialysis and transplant), some treatments including dietary control, drug therapy with a spherical carbonaceous absorbent, and anti-hypertensive drugs including ACEIs (angiotensin converting enzyme inhibitors) and ARBs (angiotensin receptor blockades) have shown some inhibition of the progression of CRF. These treatments are still not effective enough to curtail this increase. Therefore, the development of new effective drugs preventing the progression of CRF is still urgently required. In the present article, we show the first indication that Uremic Clearance Granule could be such a candidate.Uremic Clearance Granule (Niaoduqing Keli in Chinese) (GUANGZHOU CONSUN PHARMACEUTICAL CO., LTD, CHINA) is one of traditional Chinese herbal medicine having been used for treatment of CRF in clinic for many years. To explore the mechanism relates to therapeutic effects of Uremic Clearance Granules on CRF and provide the academic evidences for clinical application, we had done some researches at DNA methylation modification, key gene mRNA and protein expression and disease-related metabolic products three levels using the Wister rats as the CRF model. The major results are shown as following:Firstly, we examined the mRNA expression of the TGF-β1 and its downstream genes by SYBR Green Real-time fluorescent quantitative PCR, the protein expression of the TGF-β1 gene by Immunohistochemistry. A high level of TGF-(31 protein and mRNAs expression were identified in pathological control group while the level of TGF-β1 protein and mRNAs expression decreased comparatively in Uremic Clearance Granule-treatment group. The methylation status of TGF-β1 promoter in three groups was analyzed by methylation-specific PCR. There were three loci demethylated in TGF-β1 promoter of pathological rats, they were remathylated in Uremic Clearance Granule treatment group. The results showed that the treatment mechanism of Uremic Clearance Granule on CRF was to reduce expression of multiple genes which take the gene TGF-β1 as the center.Secondly, Uremic Clearance Granule treatment could reduce the Homocysteine in rats blood, relieve Hyperhomocysteinemia (hHcys). The prevalence of hHcys in CRF patients is 82.5%, which is 2 to 3 times of normal level. Clinical and experimental studies suggested that hHomocysteine is also a risk factor for CRF. The Homocysteine (Hey) concentration in three different groups was determined by High Performance Liquid Chromatography. The data showed that the homocysteine concentration in Uremic Clearance Granule treatmeat rats reduced obviously compared to that in pathological control rats. The results indicate that Uremic Clearance Granule restore the renal function by homoeysteine clearing.Thirdlv, the data showed that Uremic Clearance Granule restored genomic DNA methvlation to normal level. The accumulation of Homoevsteine in vivo leads to abnormal DNA methylation. Compared with normal control rats, we found the renal genomic DNA hypomethylation in pathological rats by MSAP analysis. Uremic Clearance Granule therapy restored it to normal level. The results reveal epigenetic mechanisms of Uremic Clearance Granule for treatment on Chronic Renal Failure.As a summary, we educed that Uremic Clearance Granule treatment could clear the Homocysteine, restore DNA methylation to normal level and correct the patterns of gene expression. Clearance of Homocysteine has leaded to recovery of some genes methylation status may be one of molecular mechanisms of Uremic Clearance Granule as an effective treatment for CRF.
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