Defining human diabetic nephropathy on the molecular level: Integration of transcriptomic profiles with biological knowledge

Martini, Sebastian; Eichinger, Felix; Nair, Viji; Kretzler, Matthias

doi:10.1007/s11154-008-9103-3

Cited by 72 publications

(60 citation statements)

References 51 publications

(52 reference statements)

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“…3 Furthermore, a recent observational study suggests that inhibition of inflammasome signaling improves renal function (on the basis of a decline in serum creatinine) in patients with established dNP. 18 Likewise, the data obtained from the Nephromine dataset 19 demonstrate that inflammasome, but not apoptosis, regulators are induced in glomeruli of patients with diabetes, which further supports a crucial role of inflammasome activation for dNP, not only in rodents, but also in humans.…”

mentioning

confidence: 63%

Caspase-1, but Not Caspase-3, Promotes Diabetic Nephropathy

Shahzad

Bock

Al‐Dabet

et al. 2016

JASN

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Glomerular apoptosis may contribute to diabetic nephropathy (dNP), but the pathophysiologic relevance of this process remains obscure. Here, we administered two partially disjunct polycaspase inhibitors in 8-week-old diabetic (db/db) mice: M-920 (inhibiting caspase-1, -3, -4, -5, -6, -7, and -8) and CIX (inhibiting caspase-3, -6, -7, -8, and -10). Notably, despite reduction in glomerular cell death and caspase-3 activity by both inhibitors, only M-920 ameliorated dNP. Nephroprotection by M-920 was associated with reduced renal caspase-1 and inflammasome activity. Accordingly, analysis of gene expression data in the Nephromine database revealed persistently elevated glomerular expression of inflammasome markers (NLRP3, CASP1, PYCARD, IL-18, IL-1b), but not of apoptosis markers (CASP3, CASP7, PARP1), in patients with and murine models of dNP. In vitro, increased levels of markers of inflammasome activation (Nlrp3, caspase-1 cleavage) preceded those of markers of apoptosis activation (caspase-3 and -7, PARP1 cleavage) in glucosestressed podocytes. Finally, caspase-3 deficiency did not protect mice from dNP, whereas both homozygous and hemizygous caspase-1 deficiency did. Hence, these results suggest caspase-3-dependent cell death has a negligible effect, whereas caspase-1-dependent inflammasome activation has a crucial function in the establishment of dNP. Furthermore, small molecules targeting caspase-1 or inflammasome activation may be a feasible therapeutic approach in dNP.

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mentioning

confidence: 63%

Caspase-1, but Not Caspase-3, Promotes Diabetic Nephropathy

Shahzad

Bock

Al‐Dabet

et al. 2016

JASN

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“…Likewise, glomerular lipid accumulation and mesangial matrix expansion was increased in non-diabetic Lxrα/β −/− mice compared with Lxrα/β +/+ mice. This new model of renal disease may be relevant to human disease, since the expression of LXRα and LXRβ is significantly decreased in patients with DN compared with controls [27] and renal biopsies from patients with DN show lipid deposition primarily in glomeruli [41][42][43]. Recent studies looking at LXR action in the kidney have shown improved albuminuria with other LXR ligands (T091317, GW3965) and different animal models of DN (STZ C57Bl/6, STZ Ldlr −/− ) [28,29]; however, these studies were unable to address the importance of LXR in baseline renal function.…”

Section: Discussionmentioning

confidence: 99%

“…Human biopsies and experimental rodent models have revealed a consistent downregulation of LXRs in DN compared with control [26,27], and experiments with firstgeneration LXR ligands have shown anti-inflammatory and anti-albuminuric actions in diabetic mice [28,29]. While these observations are promising for the development of DN therapies targeting LXRs, several fundamental questions remain.…”

Section: Introductionmentioning

confidence: 99%

Liver X receptors preserve renal glomerular integrity under normoglycaemia and in diabetes in mice

et al. 2013

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Aims/hypothesis Liver X receptors (LXRs) α and β are nuclear hormone receptors that are widely expressed in the kidney. They promote cholesterol efflux from cells and inhibit inflammatory responses by regulating gene transcription. Here, we hypothesised (1) that LXR deficiency would promote renal decline in a mouse model of diabetes by accelerating intraglomerular cholesterol accumulation and, conversely, (2) that LXR agonism would attenuate renal decline in diabetes.Methods Diabetes was induced with streptozotocin (STZ) and maintained for 14 weeks in Lxrα/β +/+ (Lxrα, also known as Nr1h3; Lxrβ, also known as Nr1h2) and Lxrα/β −/− mice. In addition, STZ-injected DBA/2J mice were treated with vehicle or the LXR agonist N ,N -dimethyl-hydroxycholenamide (DMHCA) (80 mg/kg daily) for 10 weeks. To determine the role of cholesterol in diabetic nephropathy (DN), mice were placed on a Western diet after hyperglycaemia developed. Results Even in the absence of diabetes, Lxrα/β −/− mice exhibited a tenfold increase in the albumin:creatinine ratio and a 40-fold increase in glomerular lipid accumulation compared with Lxrα/β +/+ mice. When challenged with diabetes, Lxrα/β −/− mice showed accelerated mesangial matrix expansion and glomerular lipid accumulation, with upregulation of inflammatory and oxidative stress markers. In the DN-sensitive STZ DBA/2J mouse model, DMHCA treatment significantly decreased albumin and nephrin excretion (by 50% each), glomerular lipids and plasma triacylglycerol (by 70%) and cholesterol (by 48%); it also decreased kidney inflammatory and oxidative stress markers compared with vehicle-treated mice. Conclusions/interpretation These data support the idea that LXR plays an important role in the normal and diabetic kidney, while showing that LXR, through its inhibitory effect on inflammation and cholesterol accumulation in glomeruli, could also be a novel therapeutic target for DN.

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“…Unprocessed gene expression datasets are available in the Gene Expression Omnibus and have also been integrated into the renal search engine Nephromine (www.nephromine.org) for additional systems biology analysis by the renal research community. 39 GWAS, intrarenal transcriptional profiles, and biologic knowledge together were able to define a tight pathway-crosstalk activated Figure 4. CKD associated pathways are shared between renal diseases.…”

Section: The Ckd Pathway Network As a Resource For The Renal Researchmentioning

confidence: 99%

Integrative Biology Identifies Shared Transcriptional Networks in CKD

Martini

Nair

Keller

et al. 2014

Journal of the American Society of Nephrology

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118

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A previous meta-analysis of genome-wide association data by the Cohorts for Heart and Aging Research in Genomic Epidemiology and CKDGen consortia identified 16 loci associated with eGFR. To define how each of these single-nucleotide polymorphisms (SNPs) could affect renal function, we integrated GFRassociated loci with regulatory pathways, producing a molecular map of CKD. In kidney biopsy specimens from 157 European subjects representing nine different CKDs, renal transcript levels for 18 genes in proximity to the SNPs significantly correlated with GFR. These 18 genes were mapped into their biologic context by testing coregulated transcripts for enriched pathways. A network of 97 pathways linked by shared genes was constructed and characterized. Of these pathways, 56 pathways were reported previously to be associated with CKD; 41 pathways without prior association with CKD were ranked on the basis of the number of candidate genes connected to the respective pathways. All pathways aggregated into a network of two main clusters comprising inflammation-and metabolism-related pathways, with the NRF2-mediated oxidative stress response pathway serving as the hub between the two clusters. In all, 78 pathways and 95% of the connections among those pathways were verified in an independent North American biopsy cohort. Disease-specific analyses showed that most pathways are shared between sets of three diseases, with closest interconnection between lupus nephritis, IgA nephritis, and diabetic nephropathy. Taken together, the network integrates candidate genes from genome-wide association studies into their functional context, revealing interactions and defining established and novel biologic mechanisms of renal impairment in renal diseases.

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Defining human diabetic nephropathy on the molecular level: Integration of transcriptomic profiles with biological knowledge

Cited by 72 publications

References 51 publications

Caspase-1, but Not Caspase-3, Promotes Diabetic Nephropathy

Caspase-1, but Not Caspase-3, Promotes Diabetic Nephropathy

Liver X receptors preserve renal glomerular integrity under normoglycaemia and in diabetes in mice

Integrative Biology Identifies Shared Transcriptional Networks in CKD

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