Pharmacology network was used to investigate the common key target and signaling pathway of Notoginseng Radix et Rhizoma in the protection against diabetic nephropathy(DN), diabetic encephalopathy(DE) and diabetic cardiomyopathy(DCM). The chemical components of Notoginseng Radix et Rhizoma were obtained through TCMSP database and literature mining, and SwissTargetPrediction database was used to predict potential targets of Notoginseng Radix et Rhizoma. The disease targets of DN, DE and DCM were obtained through OMIM and GeneCards databases. The overlapped targets of component targets and disease targets of DN, DE and DCM were obtained, and the network of "chemical component-target-disease" was established. The enriched GO and KEGG of the overlapped genes were investigated by using ClueGo plug-in with Cytoscape. At the same time, the PPI network was constructed through STRING database, and the common key targets for the treatment of three diseases by Notoginseng Radix et Rhizoma were obtained through topological parametric mathematical analysis by Cytoscape. A total of 166 chemical components and 835 component targets were screened out from Notoginseng Radix et Rhizoma. Briefly, 216, 194 and 230 disease targets of DN, DE and DCM were collected, respectively. And 54, 45 and 57 overlapped targets were identified when overlapping these disease targets with component targets of Notoginseng Radix et Rhizoma, respectively. Enrichment analysis indicated that the AGE-RAGE signaling pathway and FoxO signaling pathway were the common pathways in the protection of Notoginseng Radix et Rhizoma against DN, DE and DCM. Network analysis of the overlapped targets showed that TNF, STAT3, IL6, VEGFA, MAPK8, CASP3 and SIRT1 were identified as key targets of Notoginseng Radix et Rhizoma against DN, DE and DCM, the selected key targets were verified by literature review, and it was found that TNF, IL6, VEGFA, CASP3 and SIRT1 had been reported in the literature. In addition, there were the most compounds corresponding to the commom core target STAT3, indicating that more compounds in Notoginseng Radix et Rhizoma could regulate STAT3. This study indicated that Notoginseng Radix et Rhizoma potentially protected against DN, DE and DCM through regulating AGE-RAGE signaling pathway and FoxO signaling pathway and 7 common targets including TNF, STAT3, IL6, VEGFA, MAPK8, CASP3 and SIRT1. This study provided a reference for the research of "different diseases with same treatment" and also elucidated the potential mechanism of Notoginseng Radix et Rhizoma against DN, DE and DCM.
Brain Diseases ; Diabetes Mellitus ; Diabetic Cardiomyopathies/genetics* ; Diabetic Nephropathies/genetics* ; Humans ; Research Design ; Signal Transduction

This study investigated the protective effects of Moutan Cortex polysaccharides components(MCPC) on the renal tissues of diabetic nephropathy(DN) rats and explored their regulation effect on inflammatory response and oxidative stress. The DN rat model was induced by high-glucose and high-fat diet combined with streptozotocin(STZ), and then the rats were randomly divided into control group, model group, positive group and MCPC high(120 mg·kg~(-1)·d~(-1)), low(60 mg·kg~(-1)·d~(-1)) dose groups. After 12 weeks treatment, blood was taken from the orbit of the rats, and then they were sacrificed before the kidney tissues were collected. The serum and tissues were detected for related biochemical indicators and pathological changes of the kidney. Immunohistochemical methods were used to determine the expression of FN and ColⅣ in the kidney tissue of DN rats. Compared with the model group, blood glucose, serum creatinine, blood urea nitrogen and 24 h urine protein in the MCPC high-dose group were significantly reduced(P<0.01). The results of HE, PAS, Masson staining showed that glomerular basement membrane thickening, Bowman's capsule narrowing and inflammatory cell infiltration in DN rats were improved in the MCPC high-dose group; the activity of T-SOD and GSH-Px in serum significantly increased(P<0.001), and the expression level of FN significantly decreased(P<0.001). The high-dose MCPC treatment could effectively inhibit the abnormal expression of Col Ⅳ(P<0.001) and significantly reduce the levels of AGEs and RAGE in serum(P<0.001), the content of VCAM-1 and IL-1β in serum(P<0.001), and the levels of IL-1β mRNA in kidney tissue(P<0.001), but failed to effectively reduce VCAM-1 mRNA levels in kidney tissues. The high-dose MCPC could significantly improve pathological injury of renal tissue and related renal indicators in DN rats, and achieve renal protection in DN rats mainly by regulating oxidative stress and inflammatory factors.
Animals ; Diabetes Mellitus, Experimental/genetics* ; Diabetic Nephropathies/genetics* ; Drugs, Chinese Herbal ; Kidney ; Paeonia ; Polysaccharides/pharmacology* ; Rats

Adult ; Diabetic Nephropathies ; genetics ; pathology ; Disease Progression ; Female ; Humans ; Male ; Middle Aged ; Transcriptome ; genetics

This study aimed to investigate the effects of geniposide(GP) on the expression of prokineticin(PK2) and prokineticin receptor 1(PKR1) in db/db mice with diabetic nephropathy(DN), so as to explore how the PK2 signaling pathway participated in the pathological changes of DN and whether GP exerted the therapeutic effect through this signaling pathway. Male mice were randomly divided into four groups, namely db/m, db/db, db/db+GP, and db/m+GP groups, with five in each group. The mice in the db/db+GP and db/m+GP groups were gavaged with 150 mg·kg~(-1) GP for eight successive weeks. Afterwards, all the mice were sacrificed and the renal tissues were embedded. The morphological changes in glomerulus and renal tubules were observed by Masson and PAS staining. The expression levels of PK2, PKR1, and Wilm's Tumor Protein 1(WT_1) in podocytes were detected by immunohistochemistry, and the protein expression levels of PK2 and PKR1 in mouse kidney by Western blot. The morphological results showed serious glomerular and tubular fibrosis(Masson), high glomerular and tubular injury score(PAS), increased glomerular mesangial matrix, thickened basement membrane, exfoliated brush border of renal tubules, decreased WT_1 in glomerular podocytes, and massive loss of podocytes in the db/db group. After administration with GP, the glomerular and tubular fibrosis was alleviated, accompanied by improved glomerular basement membrane and renal tubule brush edge, and up-regulated WT_1. As revealed by further protein detection, in the db/db group, the expression levels of PK2 and PKR1 and p-Akt/Akt ratio declined, whereas the ratio of Bax/Bcl-2 rose. Ho-wever, PKR2 and p-ERK/ERK ratio did not change significantly. After administration with GP, the PK2 and PKR1 expression was elevated, and p-Akt/Akt ratio was increased. There was no obvious change in PKR2, Bax/Bcl-2 ratio, or p-ERK/ERK ratio. All these have demonstrated that GP improves the renal damage in DN mice, and PK2/PKR1 signaling pathway may be involved in such protection, which has provided reference for clinical treatment of DN with GP.
Animals ; Diabetes Mellitus ; Diabetic Nephropathies/genetics* ; Iridoids ; Kidney ; Male ; Mice ; Signal Transduction

OBJECTIVE: To explore the influence of long non-coding (lnc) RNA Gm15645 on the podocyte injury in mice with diabetic nephropathy. METHODS: Male db/db mice (with Type 2 diabetes) with a genetic background of C57BLKs/J and db/m mice (healthy) born in littermates were randomly divided into three groups. db/db group was injected with lncRNAGm15645 shRNA lentivirus with a podocyte-specific marker NPHS2; db/db blank group was injected with saline, and db/db control group was injected withnon-sense lentivirus. The results of PAS staining, pathological changes of renal tissue, relative expression of GSK-3beta, and podocin expression were compared. RESULTS: lncRNAGm15 645 was overexpressed and podocin was down-regulated in the lentivirus overexpressed group. Mesangial cell proliferation, mesangial matrix hyperplasia, thickened basement membrane, widely fused foot process, and podocyte injury were observed by PAS staining. The expression of Gm15645 in the db/db group was significantly lower than that of the db/db blank group and db/db control group (P< 0.05), while the expression of podocin was higher (P< 0.05). Gm15645 was co-stained with podocin in renal tissue, and the target gene was GSK-3beta. CONCLUSION lncRNAGm15645 may provide an early biomarker for the occurrence of podocyte injury in diabetic nephropathy. The mechanism may be related to the feedback regulation of GSK-3beta gene.
Animals ; Diabetes Mellitus, Type 2 ; Diabetic Nephropathies/genetics* ; Glycogen Synthase Kinase 3 beta ; Male ; Mice ; Podocytes ; RNA, Long Noncoding/genetics*

OBJECTIVETo investigate the association between single nucleotide polymorphisms (SNP) of angiopoietin-2 (Ang-2) gene and type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN).

METHODSGenotype and allele frequency of Ang-2 were detected by amplification refractory mutation system-PCR(ARMS-PCR) in 221 cases with T2DM and 104 normal controls. Monocyte chemoattractant protein-1(MCP-1) was measured by ELISA. DN patients were divided into three groups according to urinary albumin excretion rates (UAER), i.e. DN0: UAER < 30 mg/24 h, DN1: UAER 30-300 mg/24 h and DN2: UAER > 300 mg/24 h.

RESULTSStatistics showed: (1) Genotype frequencies and allele frequencies in Ang-2 1233A/G had significant difference but not Ang-2 759T/G and 1078A/G; (2) Comparing with those with genotype AA, the relative risk of genotype (AG+ GG) suffered from T2DM and DN were 2.265 fold (OR= 2.265, 95% CI: 1.223-1.402, P= 0.031), 1.789 fold (OR= 1.789, 95% CI: 0.889-1.021, P= 0.012), respectively; (3) The onset of DN was related to Ang-2 1233A/G allele G (r= 1.321, OR= 1.427, 95% CI: 2.324-4.177, P= 0.034).

CONCLUSIONAng-2 1233A/G polymorphism may be associated with T2DM and involved in onset and development of DN.

Angiopoietin-2 ; genetics ; Case-Control Studies ; Chemokine CCL2 ; genetics ; Diabetes Mellitus, Type 2 ; genetics ; Diabetic Nephropathies ; genetics ; Gene Frequency ; Genotype ; Humans ; Polymorphism, Single Nucleotide

OBJECTIVETo investigate the relationship of Chinese medicine syndrome pattern with urinary albumin excretion rate (UAER) and its related factors in patients with diabetic nephropathy (DN).

METHODSSixty-three early stage DN patients were subjected to the study, the Chinese medicine syndrome patterns were differentiated, and their condition of methylene tetrahydrofolate reductase (MTHFR) C677T mutation was detected (shown by gene polymorphism of 677 base pairs). Meantime, plasma levels of homocysteine (Hcy), folic acid, fasting and postprandial glucose (FG and PG), glycohemoglobin (HbA1c), blood lipids as well as UAER were measured.

RESULTSSyndrome pattern was differentiated as yin-deficiency with heat-flourishing in 17 patients, qi-yin deficiency in 24, and yin-yang deficiency in 22; while accompanied blood stasis syndrome (BSS) was found in 35. Gene polymorphism detection indicated that 19 patients were of CC-type, 17 of TT-type, and 27 of CT-type. Analysis showed that higher UAER level often revealed in patients with BSS, as compared with that in patients of non-BS pattern, the difference was statistically significant (P < 0.05). UAER levels in patients of different genotypes were insignificantly different (P > 0.05), but showed a linear regressive relation, namely positively correlated with Hcy level in patients of isogeneic type (r = 0.674, P < 0.05). No statistical significance was found between levels of UAER and other related factors (P > 0.05).

CONCLUSIONUAER level in early stage DN patients of BSS pattern is rather higher, and it shows a linear regression relationship (positive correlation) with Hcy level in patients of isogeneic type.

Adult ; Aged ; Albuminuria ; physiopathology ; Diabetic Nephropathies ; genetics ; physiopathology ; urine ; Diagnosis, Differential ; Female ; Homocysteine ; blood ; Humans ; Male ; Medicine, Chinese Traditional ; Methylenetetrahydrofolate Reductase (NADPH2) ; genetics ; Middle Aged ; Polymorphism, Genetic

OBJECTIVETo investigate whether the angiotensin II type I receptor gene (AGTR1) A1166C polymorphism is associated with a high risk of diabetic nephropathy.

METHODSThe allele frequency and the genotype distribution of the AGTR1 A1166C polymorphism were studied in normal controls (157 cases), simple diabetes (141 cases, duration of diabetes >10 years), and diabetic nephropathy (152 cases) by means of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).

RESULTSPatients with diabetic nephropathy had a higher frequency of C allele of the AGTR1 A1166C polymorphism than that of normal controls and simple diabetes (P<0.05); but there was no significant difference in frequency of C allele between the normal controls and patients with simple diabetes.

CONCLUSIONThe diabetic patients with AGTR1 C allele may be more susceptible to diabetic nephropathy than diabetic patients with A allele.

Aged ; Diabetic Nephropathies ; genetics ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Polymorphism, Genetic ; Receptor, Angiotensin, Type 1 ; genetics

The angiotensin-converting enzyme (ACE) gene DD homozygote has been suggested to be a significant risk factor for the progression of diabetic nephropathy. We analyzed clinical parameters and ACE genotype distribution between type 2 diabetic patients at the extremes of renal risk, i.e. an end-stage renal failure (ESRF) group (n = 103, group 1) who were on dialysis therapy due to progression of diabetic nephropathy, and a no progression group (n = 88, group 2) who had maintained normal renal function and normoalbuminuria for more than 15 years. There were no significant differences in age, sex, body mass index, HbA1c level, or lipid profiles between the two groups (p > 0.05). Group 1 had a significantly higher prevalence of hypertension [group 1: 82.5% (85/103) vs. group 2: 50.0% (44/88), p < 0.05] and diabetic retinopathy [group 1: 103/103 (100%) vs. group 2: 28/88 (31.8%), p < 0.05] than group 2. Daily urinary albumin excretion was also higher in group 1 than in group 2 [group 1: 2873 +/- 2176 mg/day vs. 12 +/- 7 g/day, p < 0.05]. The frequencies of the DD, ID, and II genotypes of the ACE gene in group 1 and group 2 were 26.2%, 47.6%, and 26.2%, and 7.9%, 57.9%, and 34.2%, respectively. The ACE genotype frequencies between the two groups were significantly different according to a chi-square test with Bonferroni's correction (p = 0.004). The presence of the DD genotype increased the risk of ESRF 4.286-fold compared to the II genotype [odds ratio 4.286, 95% CI 1.60- 11.42, p = 0.005]. The frequency of the D-allele was higher in both male and female patients in group 1 compared to group 2, but reached statistical significance only in males [male, group 1: 50.8% vs. group 2: 35.0%, p = 0.018, female, group 1: 48.8% vs. group 2: 39.5%, p = 0.231]. This study, although limited by sample size, showed that type 2 diabetic ESRF patients more frequently expressed the DD genotype. These findings may substantiate the previously noted relationship between the ACE DD genotype and the progression of diabetic nephropathy in Korean type 2 diabetic patients.
Renal Dialysis ; *Polymorphism, Genetic ; Peptidyl-Dipeptidase A/*genetics/metabolism ; Middle Aged ; Male ; Kidney Failure, Chronic/diagnosis/*genetics ; Humans ; Homozygote ; Gene Frequency ; Female ; Diabetic Nephropathies/diagnosis/*genetics ; Diabetes Mellitus, Type 2/diagnosis/*genetics ; Aged

OBJECTIVETo explore the association of Chinese medicine constitution susceptibility to diabetic nephropathy (DN) and transforming growth factor (TGF)-β1 (T869C) gene polymorphism.

METHODSTGF-β1 gene polymorphism detected with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was screened for 180 DN cases and 180 type 2 diabetic mellitus (T2DM) cases without combined DN. Patients with DN were surveyed epidemiologically with constitution in the Chinese medicine questionnaire (CCMQ). Binary logistic regression analysis was utilized to study the correlation between nine types of Chinese medicine constitution and TGF-β1 (T869C) gene polymorphisms.

RESULTSThe DN group has a higher frequency of TGF-β1 (T869C) gene polymorphism than the T2DM group, and CC/CT genotypes than the T2DM group [CC, CT, TT (DN group): 88, 87, 5 (cases) versus (T2DM group) 71, 73, 36 (cases), P<0.05]. The phlegm-dampness constitution, damp-heat constitution, and blood stasis constitution have correlations with TGF-β1 (T869C) gene polymorphism.

CONCLUSIONChinese medicine constitutions were associated with TGF-β1 (T869C) gene polymorphism, a potential predictor of susceptibility to DN in T2DM patients.

Aged ; Body Constitution ; genetics ; Diabetic Nephropathies ; genetics ; Female ; Genetic Predisposition to Disease ; Health Surveys ; Humans ; Logistic Models ; Male ; Medicine, Chinese Traditional ; Polymorphism, Single Nucleotide ; genetics ; Transforming Growth Factor beta1 ; genetics