Preventive And Therapeutic Effects Of Iridiod Glycosides From Paedeira Scandens On Uric Acid Nephropathy In Rats And Its Mechanisms

Uric acid nephropathy (UAN) also known as gouty nephropathy is mainly caused byexcessive uric acid generation or decreased excretion of uric acid in the kidney, whichresults in damage of renal tissue. Iridiod Glycosides from Paederia Scandens (LOUR.)MERRILL (Rubiaceae)(IGPS) are asperuloside, paederoside, scandoside et al. Ourprevious studies suggested that treatment with IGPS could reduce serum urate levelsand relieve symptoms in UAN rats with inflammation. The present study is to furtherexplore the preventive and therapeutic effects of IGPS and its possible mechanism onUAN rats.The main experimental results are as follow:1Animal model of uric acid nephropathy rats and preventive and therapeuticeffects of iridiod glycosides from paederia scandensThe experimental animal model of UAN was made by orally administering yeastextract paste (15g/kg, bid×42d) and intraperitoneal injection of potassium oxonate(PO)(250mg/kg, qw×6w). Every day during the experiment to observe the demeanor of furcolor in rats, fed into the water, urine and behaviors and so on. With ig of0days,7d,14d,28d,35d and42d to monitor changes in body weight in rats, respectively.Simultaneously using a tail-cuff sphygmomanometer with an automated systemphotoelectric sensor to investigate Systolic BP (SBP) changes of UAN rats at0~6weeks.IGPS(280,140,70mg/kg) and AP group (50mg/kg) were orally administered oncedaily at evening since the8th day of the modeling process. After6weeks of modeling,the rats in each group of serum uric acid (UA), blood urea nitrogen(BUN), serumcreatinine(Cre), fractional excretion of urate (FEUA) and renal indices are examined. Rat kidneys are stained with hematoxylin and eosin(HE) for conventionalmorphological evaluation.The results show that IGPS (280,140mg/kg, ig, qd×35d) could significantlyimprove the uric acid nephropathy in rats in general symptoms, could promote thegrowth of body weight, significantly decrease SBP, lower blood UA content, improverenal function, increase fractional excretion of urate and lower renal index. IGPS (280,140mg/kg) could attenuate kidney damages in various extents, consisting of preventingthe increase in urate crystals and inflammatory cellular influx in the tubule andcollecting duct. Meanwhile, the tubular dilatation and interstitial fibrosis was alleviated.These findings indicate that IGPS has good preventive and therapeutic effect on uricacid nephropathy induced by yeast and potassium oxonate in rats.2Preventive and therapeutic effects of iridiod glycosides from paederia scandenson uric acid nephropathy rats and its mechanisms2.1Effects of IGPS on hypertension in UAN ratsUsing a Dinamap BP monitor to observe Systolic BP (SBP) changes of UAN ratsat0~6weeks with twice measurements for per week. During the5-week treatment,IGPS (280,140mg/kg) could significantly decrease SBP. In the model group rats, thelevel of NOS-1proteins examined by immunohistochemistry in the macula densadecreased visibly, however, IGPS(280,140mg/kg) significantly enhanced the level ofNOS-1, indicating that IGPS could preserve immunoreactivity of NOS-1, which mayinhibite hypertension and may be an important cause of its renal protection in UAN rats.2.2Effect of IGPS on uric acid metabolism in UAN ratsPhosphotungstic acid method was used to determine urine uric acid, urine creatinine,and urine volume levels in UAN rats, and uric acid excretion in rats was calculated. Theresults showed that IGPS (280,140mg/kg, ig, qd×35d) could significantly increase theuric acid nephropathy in rats’ urine uric acid levels, IGPS (280mg/kg, ig, qd×35d)could increase the uric acid nephropathy in rats urine creatinine and urine volume, and IGPS (280,140mg/kg, ig, qd×35d) could enhancement urate clearance of uric acid inUAN rats. These results suggest that the uric acid nephropathy effect is partly due toincrease uric acid clearance in UAN rats.2.3Effect of IGPS on inflammatory cytokines in UAN ratsThe COX-2and TNF-α protein expression were investgated byimmunohistochemistry, TNF-α mRNA levels were monitored by RT-PCR. The resultsshowed that IGPS (280,140mg/kg, ig, qd×35d) could significantly reduce the COX-2and TNF-α protein expression in UAN rats kidney tissue, and reduce the expression ofTNF-α mRNA. This evidences showed IGPS could effectively protect the inflammatorycytokines mediated tubulointerstitial injury, which may be an important mechanisms ofits renal protection in UNA rats.2.4Effect of IGPS on fibrosis in UAN rats kidney tissueThe TGF-β1protein expression was investgated by immunohistochemistry and theTGF-β1mRNA levels were monitored by RT-PCR. The results showed that IGPS (280,140mg/kg, ig, qd×35d) could down-regulate TGF-β1protein expression and TGF-β1mRNA expressions. These results showed IGPS could effectively improve renal fibrosison UAN rats.Conclusion: IGPS has good preventive and therapeutic effect on uric acid nephropathyrat model induced by yeast and potassium oxonate, and its mechanisms might be relatedto decrease serum uric acid, inhibit SBP level, to accelerate uric acid clearance, improvekidney inflammation and restrain the degree of renal fibrosis.