Diabetic nephropathy: is ESRD its only heritable phenotype?
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ABSTRACT:
SUBMITTER: Pezzolesi MG
PROVIDER: S-EPMC3785288 | biostudies-literature | 2013 Oct
REPOSITORIES: biostudies-literature
Publications
Diabetic nephropathy: is ESRD its only heritable phenotype?
Pezzolesi Marcus G MG Krolewski Andrzej S AS
Journal of the American Society of Nephrology : JASN 20130912 10
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Project description:Transcriptional profiling of human PBMCs comparing healthy controls, patients with diabetic nephropathy and patients with ESRD. PBMCs were analyzed as they mediate inflammatory injury. Goal was to determine effects of increasing severity of diabetic nephropathy on global PBMC gene expression. Microarray analysis of PBMCs taken from patients with varying degrees of diabetic nephropathy.
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Project description:Human PBMCs: Healthy vs Diabetic nephropathy vs ESRD
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Project description:Gene expression profiling in glomeruli from human kidneys with diabetic nephropathy Keywords = Diabetes Keywords = kidney Keywords = glomeruli Keywords: other
2004-04-01 | GSE1009 | GEO
Project description:IntroductionFamilial IgA nephropathy (IgAN) has been widely reported. However, its clinicohistologic characteristics and long-term prognosis are not clear.MethodsA total of 348 familial IgAN cases from 167 independent families were recruited and their clinicohistologic characteristics as well as lifetime risk of end-stage renal disease (ESRD) were compared to 1116 sporadic IgAN patients from the same geographic region.ResultsOf all familial IgAN patients, 60 (17%) came from 32 single-generation (SG; all affected individuals are siblings) families, whereas 286 (82%) came from 134 multiple-generation (MG; affected individuals were present in at least 2 consecutive generations) families. The lifetime ESRD risk was significantly higher in familial patients than sporadic ones after adjusting by gender (hazard ratio [HR]=1.40, 95% confidence interval [CI]: 1.12-1.74, P = 0.004), with 5 years younger in median ESRD age (60 years vs. 65 years in familial and sporadic cases separately). Interestingly, among familial patients, we found cases from SG families (vs. MG families: HR = 2.62, 95% CI: 1.59-4.31, P < 0.001) or with early onset (onset age <30 years) (vs. late onset: HR = 4.79, 95% CI: 3.16-7.26, P < 0.001) had higher lifetime ESRD risk. Furthermore, among sporadic patients, men had lower estimated glomerular filtration rate (eGFR), higher urine protein, higher Oxford T score, and higher risk for life span ESRD compared with women (male vs. female, 25% vs. 17%, P = 0.003) whereas these gender differences were not seen in familial patients.ConclusionFamilial IgAN cases had poorer renal outcomes and less gender differences compared with sporadic cases. These findings provide evidence that familial disease represent a distinct subtype of more progressive IgAN. Early diagnosis could improve the prognosis of cases with familial IgAN.
| S-EPMC7783566 | biostudies-literature
Project description:This study aimed to examine the macrophage phenotype and its relationship to renal function and histological changes in human DN and the effect of TREM-1 on high-glucose-induced macrophage activation. We observed that in renal tissue biopsies, the expression of CD68 and M1 was apparent in the glomeruli and interstitium, while accumulation of M2 and TREM-1 was primarily observed in the interstitium. The numbers of CD68, M1, and M2 macrophages infiltrating in the DN group were increased in a process-dependent manner compared with the control group, and the intensities of the infiltrates were proportional to the rate of subsequent decline in renal function. M1 macrophages were recruited into the kidney at an early stage (I+IIa) of DN. The M1-to-M2 macrophage ratio peaked at this time, whereas M2 macrophages predominated at later time points (III) when the percentage of M1/M2 macrophages was at its lowest level. In an in vitro study, we showed that under high glucose conditions, macrophages began to up-regulate their expression of TREM-1, M1, and marker iNOS and decreased the M2 marker MR. However, the above effects of high-glucose were abolished when TREM-1 expression was inhibited by TREM-1 siRNA. In conclusion, our study demonstrated that there was a positive correlation between the M1/M2 activation state and the progress of DN, and TREM-1 played an important role in high-glucose-induced macrophage phenotype transformation.
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Project description:Validation of predicted gene expression of human mesangial cells after 24h Tacrolimus stimulus Objective: To evaluate tacrolimus as therapeutic option for diabetic nephropathy (DN) based on molecular profile and network-based molecular model comparisons. Materials and Methods: We generated molecular models representing pathophysiological mechanisms of DN and tacrolimus mechanism of action (MoA) based on literature derived data and transcriptomics datasets. Shared enriched molecular pathways were identified based on both model datasets. A newly generated transcriptomics dataset studying the effect of tacrolimus on mesangial cells in vitro was added to identify mechanisms in DN pathophysiology. We searched for features in interference between the DN molecular model and the tacrolimus MoA molecular model already holding annotation evidence as diagnostic or prognostic biomarker in the context of DN. Results: Thirty nine molecular features were shared between the DN molecular model, holding 252 molecular features and the tacrolimus MoA molecular model, holding 209 molecular features, with six additional molecular features affected by tacrolimus in mesangial cells. Significantly affected molecular pathways by both molecular model sets included cytokine-cytokine receptor interactions, adherens junctions, TGF-beta signaling, MAPK signaling, and calcium signaling. Molecular features involved in inflammation and immune response contributing to DN progression were significantly downregulated by tacrolimus (e.g. the tumor necrosis factor alpha (TNF), interleukin 4, or interleukin 10). On the other hand, pro-fibrotic stimuli being detrimental to renal function were induced by tacrolimus like the transforming growth factor beta 1 (TGFB1), endothelin 1 (EDN1), or type IV collagen alpha 1 (COL4A1). Conclusion: Patients with DN and elevated TNF levels might benefit from tacrolimus treatment regarding maintaining GFR and reducing inflammation. TGFB1 and EDN1 are proposed as monitoring markers to assess degree of renal damage. Next to this stratification approach, the use of drug combinations consisting of tacrolimus in addition to ACE inhibitors, angiotensin receptor blockers, TGFB1- or EDN1-receptor antagonists might warrant further studies. comparison of gene expression of human mesangial cells after 24h Tacrolimus vs. Ctrl; 4 independent experiments were conducted (4xTacrolimus 24h and 4x ctrl. 24h with Drug solvent (DMSO))
2016-08-01 | E-GEOD-84908 | biostudies-arrayexpress
Project description:Pathogenetic markers of diabetic kidney disease (DKD) progression to ESRD are lacking. We characterized the prognostic value of histologic findings in DKD for time to ESRD in native kidney specimens from biopsies performed from 1995 to 2011 with diabetic glomerulosclerosis as the only glomerular disease diagnosis (n=109). Biopsy specimens were analyzed according to standard methods, including determination of diabetic nephropathy class, as defined by the Renal Pathology Society. Clinical data were extracted from electronic medical records. We used competing risk models, with death as the competing risk, to estimate subdistribution hazard ratios (HRs) for ESRD. All multivariable models included age, sex, black race, baseline eGFR, and baseline proteinuria. Pathologic characteristics achieving P<0.1 were added into successively complex models. ESRD occurred in 56% of patients, and 26% of patients died before reaching ESRD. In univariate analyses, diabetic nephropathy class was not statistically significant in predicting time to ESRD. The final multivariable model (n=106) showed a borderline association between mild mesangial expansion and decreased risk for ESRD (subdistribution HR, 0.64; 95% confidence interval, 0.40 to 1.00). Poor prognostic factors in the final model included segmental sclerosis and extracapillary hypercellularity (subdistribution HR, 2.04; 95% confidence interval, 1.36 to 3.05; and subdistribution HR, 2.21; 95% confidence interval, 1.19 to 4.11, respectively). In conclusion, we identified segmental sclerosis and extracapillary hypercellularity as novel, poor prognostic indicators of time from DKD to ESRD. Whether these indicators represent a distinct pathogenetic phenotype of DKD will require a large study with a broad spectrum of disease severity.
| S-EPMC5791055 | biostudies-literature
Project description:Validation of predicted gene expression of human mesangial cells after 24h Tacrolimus stimulus Objective: To evaluate tacrolimus as therapeutic option for diabetic nephropathy (DN) based on molecular profile and network-based molecular model comparisons. Materials and Methods: We generated molecular models representing pathophysiological mechanisms of DN and tacrolimus mechanism of action (MoA) based on literature derived data and transcriptomics datasets. Shared enriched molecular pathways were identified based on both model datasets. A newly generated transcriptomics dataset studying the effect of tacrolimus on mesangial cells in vitro was added to identify mechanisms in DN pathophysiology. We searched for features in interference between the DN molecular model and the tacrolimus MoA molecular model already holding annotation evidence as diagnostic or prognostic biomarker in the context of DN. Results: Thirty nine molecular features were shared between the DN molecular model, holding 252 molecular features and the tacrolimus MoA molecular model, holding 209 molecular features, with six additional molecular features affected by tacrolimus in mesangial cells. Significantly affected molecular pathways by both molecular model sets included cytokine-cytokine receptor interactions, adherens junctions, TGF-beta signaling, MAPK signaling, and calcium signaling. Molecular features involved in inflammation and immune response contributing to DN progression were significantly downregulated by tacrolimus (e.g. the tumor necrosis factor alpha (TNF), interleukin 4, or interleukin 10). On the other hand, pro-fibrotic stimuli being detrimental to renal function were induced by tacrolimus like the transforming growth factor beta 1 (TGFB1), endothelin 1 (EDN1), or type IV collagen alpha 1 (COL4A1). Conclusion: Patients with DN and elevated TNF levels might benefit from tacrolimus treatment regarding maintaining GFR and reducing inflammation. TGFB1 and EDN1 are proposed as monitoring markers to assess degree of renal damage. Next to this stratification approach, the use of drug combinations consisting of tacrolimus in addition to ACE inhibitors, angiotensin receptor blockers, TGFB1- or EDN1-receptor antagonists might warrant further studies.
2016-08-01 | GSE84908 | GEO
Project description:Diabetic nephropathy (DN) is the most important chronic kidney disease. We previously reported that Smad1 transcriptionally regulates the expression of extracellular matrix in DN. Phenotypic change in mesangial cells (MCs) is a key pathologic event in the progression of DN. The aim of this study is to investigate a novel mechanism underlying chondrogenic phenotypic change in MCs that results in the development of DN. MCs showed chondrogenic potential in a micromass culture, and BMP4 induced the expression of chondrocyte markers (SRY-related HMG Box 9 (SOX9) and type II collagen (COL2)). Advanced glycation end products induced the expression of chondrocyte marker proteins downstream from the BMP4-Smad1 signaling pathway in MCs. In addition, hypoxia also induced the expression of BMP4, hypoxia-inducible factor-1α (HIF-1α), and chondrocyte markers. Overexpression of SOX9 caused ectopic expression of proteoglycans and COL2 in MCs. Furthermore, forced expression of Smad1 induced chondrocyte markers as well. Dorsomorphin inhibited these inductions. Glomerular expressions of HIF-1α, BMP4, and chondrocyte markers were observed in diabetic nephropathy mice. These positive stainings were observed in mesangial sclerotic lesions. SOX9 was partially colocalized with HIF-1α and BMP4 in diabetic glomeruli. BMP4 knock-in transgenic mice showed not only similar pathological lesions to DN, but also the induction of chondrocyte markers in the sclerotic lesions. Here we demonstrate that HIF-1α and BMP4 induce SOX9 expression and subsequent chondrogenic phenotype change in DN. The results suggested that the transdifferentiation of MCs into chondrocyte-like cells in chronic hypoxic stress may result in irreversible structural change in DN.
| S-EPMC3173169 | biostudies-literature
Project description:diabetes, mouse models, diabetic nephropathy, streptozotocin db/db Keywords: other
2004-01-20 | GSE710 | GEO