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Role of Total Glucosides of Paeony in Anti-diabetic Nephropathy and Its Molecular Mechanisms Based on the Inflammation Theory

Author: WangKun
Tutor: WuYongGui
School: Anhui Medical University,
Course: Internal Medicine
Keywords: Diabetic Nephropathy Total Glucosides of Paeony Inflammation OxidativeStress Tubular epithelial-myofibroblast transdifferentiation Nephrin Macrophage Toll-like receptor Janus kinase Signal Transducers and Activators of Transcription
CLC: R259
Type: PhD thesis
Year: 2013
Downloads: 46
Quote: 0
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Abstract


Background and objectiveThe notion that chronic low-grade inflammation and activation of the innateimmune system are closely involved in the pathogenesis of diabetes mellitus hassubstantially changed our vision of this disease as a metabolic disorder in the past years.Diabetic nephropathy (DN) is a serious threat to human health. With the increase in theincidence and the prevalence of diabetes, DN is becoming more common. Pathogenesisand therapeutic intervention in DN have been the research focus in recent years.Disorder of glucose metabolism is the fundamental step in DN, resulting renalhemodynamic changes, non-enzymatic glycosylation reaction, polyol pathwayactivation, inflammation, oxidative stress, and podocyte injury, renal tubular epithelialcell transdifferentiation,protein kinase C activation, lipid metabolism disorders andgenetic background etc, are all associated with DN. Development of DN is slow andimperceptible in early stage; microalbuminuria apperance is used to be a sign of earlyDN. A number of experimental and clinical studies have demonstrated the significantrole of various inflammatory molecules in the setting of DN, including chemokines,adhesion molecules, and proinflammatory cytokines. Several works in the setting ofexperimental DN using different drugs, such as mycophenolate mofetil, methotrexate,and erythromycin, have shown that prevention of the development or amelioration ofrenal injury in diabetes was associated with anti-inflammatory actions. When diabeticpatients progress into albuminuria stage, DN becomes irreversible. So the current effortswere stressed that giving the early DN reasonable intervention to reduce the risk of entering end-stage renal failure. Paeonia lactiflora pall is a kind of Chinese traditionalherbal medicine. Effective parts and chemical constituents of TGP have been extractedand purified, their structures have been identified. TGP contains96.2%of paeoniflorinand other components such as hydroxy-paeoniflorin, glycosides of peony flower, peonylactone glycosides, benzoyl paeoniflorin etc. TGP have been extensively proven toexhibit anti-inflammatory, antioxidative, antihepatic injury and immunoregulatoryactivities without evident toxic or side-effects. In this study we established the early DNrat model and investigated the efficacy of the TGP, further explored the possiblemechanisms involving in the TGP renoprotective effects were through interfering withthe inflammatory response, oxidative stress injury, podocyte injury, renal tubularepithelial transdifferentiation and intracellular signal transduction.MethodDiabetes was induced by peritoneal injection of streptozotocin in rats.50rats wererandomly divided into normal group, control diabetic group, TGP administration groupthat was divided into three dose groups (50,100,200mg/kg.d) with daily gavaged,normal group and control diabetic group were given the same amount of solvent foreight weeks. Specimens of rat blood, urine, kidney tissue were collected, detectionindex including kidney weight, kidney weight/body weight ratio, blood glucose, serumcreatinine, urine creatinine,24h urinary albumin excretion rate (UAER), renal pathology,renal ultrastructure, renal tissue total antioxidant capacity (T-AOC), superoxidedismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-PX) using theappropriate method for testing. Indirect immunofluorescence was used to detect nephrindistribution in glomeruli. Immunohistochemical assays of transforming growth factorβ1(TGF-β1), Toll-like-receptor2(TLR2), TLR4, osteopontin protein (OPN), α-smoothmuscle actin (α-SMA), E-calcium adhesion proteins (E-cad), vimentin (Vim), ED-1,proliferating cell nuclear antigen (PCNA), signal transduction and transcription-activating factor3(STAT3), phosphorylation of STAT3(p-STAT) proteinexpressions in renal tissue. Double immunohistochemical assays of PCNA/ED-1,p-STAT3/ED-1, TLR2/ED-1, TLR4/ED-1positive cells in the renal tissue distribution.Western blotting detection of tumor necrosis factor-α (TNF-α), intercellular adhesionmolecule-1(ICAM-1), interleukin-1(IL-1), NF-κB p65, collagen type IV,3-nitrotyrosine (NT), nephrin, phosphorylation of p38MAPK (p-p38), phosphorylationof JAK2(p-JAK2) phosphorylation of STAT3(p-STAT3) protein expression in renaltissue.Results:In the control diabetic group, UAER was significantly higher than the normalgroup (P<0.01); UAER in the three TGP administration groups was significantly lowerthan the control diabetic group (P<0.01). The rats in control diabetic group manifestedas hyperglycemia, weight loss, increased relative kidney weight, TGP (50,100,200mg/kg.d) administration eight weeks had no signifcant effect in preventing the modelrats hyperglycemia and weight loss (P﹥0.01). The glomerular volume (VG) in thecontrol diabetic group was significantly higher than the normal group, in TGP (100,200mg/kg.d) administration groups the VGwere significantly lower than the controldiabetic group (P<0.05, P<0.01). In the TGP (100,200mg/kg.d) administration groupsthe tubulointerstitial injury index (TII) was significantly lower than the control diabeticgroup (P<0.05, P<0.01). The rats renal tissue expressions of ICAM-1, TNF-α, IL-1,NF-κB-p65, type IV collagen protein compared with the control diabetic group weresignificantly reduced by TGP (50,100,200mg/kg.d) administration, ICAM-1weredown47.9%,60.4%,72.9%, respectively; and TNF-α were down46.5%,86%,93.8%respectively; IL-1, were down77.7%,86.4%,88.6%, respectively; NF-κB-p65weredown38.4%,53%,59%, respectively; type IV collagen were down47.9%,60.4%,72.9%, respectively. Compared with the control diabetic group, TGP (50,100,200mg/ kg.d) administration eight weeks had no significant effect on glomerular TLR2expression, tubular-interstitial TLR2expression was significantly lower than that in thecontrol diabetic group (P<0.01). The glomerular and tubular-interstitial TLR4expressions were significantly lower by TGP (50,100,200mg/kg.d) administrationcompared with the control diabetic group (P<0.01).The renal tissue T-AOC, SOD and CAT activity in the control diabetic groupdecreased significantly compared with the normal group (P<0.01). T-AOC, SOD andCAT activity in TGP (200mg/kg.d) administration were significantly higher than thecontrol diabetic group (P<0.01). The renal tissue expression of3-NT, p-p38proteinlevels were significantly reduced by TGP (50,100,200mg/kg.d) administrationcompared with the control diabetic group,3-NT was down41.2%,43.8%,57.5%,respectively; p-p38was down30.8%,24%and60.1%, respectively. The nephrin waslinearly uniformly distributed in normal group glomeruli. Nephrin expression wassignificantly reduced, showing granular uneven distribution in control diabetic group.Nephrin expression was partially restored in the glomeruli by TGP administration.Compared with the control diabetic group the nephrin protein expression were up25.2%,89.2%,73.9%, respectively in the TGP (50,100,200mg/kg.d) administration group.The tubulointerstitial E-cad protein expression in the control diabetic group wassignificantly lower than that in the normal group (P<0.01), tubulointerstitial E-cadprotein expression was significantly higher than that in the control diabetic group byTGP (50,100,200mg/kg.d)8weeks administration (P<0.01). The tubulointerstitialα-SMA, Vim and OPN protein expression in the control diabetic group weresignificantly higher than the normal group (P<0.01), tubulointerstitial α-SMA, Vim andOPN protein expressions were significantly lower than that in the control diabetic groupby TGP (50,100,200mg/kg.d)8weeks administration (P <0.01).The PCNA, ED-1, p-STAT3, PCNA/ED-1, p-STAT3/ED-1, TLR2/ED-1,TLR4/ED-1positive staining cell number in the control diabetic group were significantly higher than that in the normal group (P<0.01). The PCNA, ED-1, p-STAT3,PCNA/ED-1, p-STAT3/ED-1positive staining cell number in TGP (50,100,200mg/kg.d) administered group were significantly lower than that in the control diabetic group(P<0.01). p-JAK2, p-STAT3protein expressions in renal tissue of the control diabeticgroup were significantly higher than that in the normal group (P<0.01). By TGP (50,100,200mg/kg.d) administration, the p-JAK2protein expressions were down22.3%,50.5%,43.2%, respectively; p-STAT3protein expressions were down20.9%,61.1%,42.3%, respectively compared to the control diabetic group.ConclusionsdfTGP has a significant protective effect on early renal damage in STZ-induceddiabetic rats. The TGP plays a renoprotective effect possiblely by following a variety ofmechanisms, such as the inhibition of intrarenal inflammatory response, anti-oxidativestress damage, inhibition of renal tubular epithelial cell transdifferentiation, inhibition ofrenal interstitial fibrosis, inhibition of macrophage infiltration and proliferation andactivation, inhibition of JAK2/STAT3signaling pathways.

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