Podocyte-specific JAK2 Overexpression Worsens Diabetic Kidney Disease in Mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE86317 | GEO | 2017/07/31
SECONDARY ACCESSION(S): PRJNA341474
REPOSITORIES: GEO
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Project description:Objective – Previous studies showed that genetic deletion or pharmacological blockade of the Receptor for Advanced Glycation Endproducts (RAGE) prevents the early structural changes in the glomerulus associated with diabetic nephropathy (DN). To overcome limitations of mouse models that lack the progressive glomerulosclerosis observed in humans, we studied the contribution of RAGE to DN in the OVE26 type 1 mouse, a model of progressive glomerulosclerosis and decline of renal function. Research Design and Methods – We bred OVE26 mice with homozygous RAGE knock out (RKO) mice and examined structural changes associated with DN and used inulin clearance studies and albumin:creatinine measurements to assess renal function. Affymetrix Mouse 430.2 microarrays were used to measure the differential expression of OVE26vsFVB(WT) mice. Transcriptional changes in the TGF-?1 and Plasminogen activator inhibitor 1 gene products were measured by pcr to investigate mechanisms underlying accumulation of mesangial matrix in OVE26 mice. Results - Deletion of RAGE in OVE26 mice reduced nephromegaly, mesangial sclerosis, cast formation, glomerular basement membrane thickening, podocyte effacement, and albuminuria. The significant 29% reduction in glomerular filtration rate observed in OVE26 mice was completely prevented by deletion of RAGE. Increased transcription of the genes for Plasminogen activator inhibitor 1, TGF-?1, TGF-? induced, ?1- (IV) collagen observed in OVE26 renal cortex significantly reduced in OVE26 RKO kidney cortex. ROCK1 activity was significantly lower in OVE26 RKO compared to OVE26 kidney cortex. Conclusions - These data provide compelling evidence for critical roles for RAGE in the pathogenesis of DN and suggest that strategies targeting RAGE in long-term diabetes may prevent loss of renal function. The differential gene expression of OVE26 (diabetics) vs FVB (nodiabetic WT) mice was measured using Affymetrix Mouse 430.2 arrays.
2011-02-22 | E-GEOD-20844 | biostudies-arrayexpress
Project description:Objective – Previous studies showed that genetic deletion or pharmacological blockade of the Receptor for Advanced Glycation Endproducts (RAGE) prevents the early structural changes in the glomerulus associated with diabetic nephropathy (DN). To overcome limitations of mouse models that lack the progressive glomerulosclerosis observed in humans, we studied the contribution of RAGE to DN in the OVE26 type 1 mouse, a model of progressive glomerulosclerosis and decline of renal function. Research Design and Methods – We bred OVE26 mice with homozygous RAGE knock out (RKO) mice and examined structural changes associated with DN and used inulin clearance studies and albumin:creatinine measurements to assess renal function. Affymetrix Mouse 430.2 microarrays were used to measure the differential expression of OVE26vsFVB(WT) mice. Transcriptional changes in the TGF-β1 and Plasminogen activator inhibitor 1 gene products were measured by pcr to investigate mechanisms underlying accumulation of mesangial matrix in OVE26 mice. Results - Deletion of RAGE in OVE26 mice reduced nephromegaly, mesangial sclerosis, cast formation, glomerular basement membrane thickening, podocyte effacement, and albuminuria. The significant 29% reduction in glomerular filtration rate observed in OVE26 mice was completely prevented by deletion of RAGE. Increased transcription of the genes for Plasminogen activator inhibitor 1, TGF-β1, TGF-β induced, α1- (IV) collagen observed in OVE26 renal cortex significantly reduced in OVE26 RKO kidney cortex. ROCK1 activity was significantly lower in OVE26 RKO compared to OVE26 kidney cortex. Conclusions - These data provide compelling evidence for critical roles for RAGE in the pathogenesis of DN and suggest that strategies targeting RAGE in long-term diabetes may prevent loss of renal function.
2011-02-22 | GSE20844 | GEO
Project description:To investigate dynamic changes in glomerular cells, including podocyte, mesangial cells and glomerular endothelial cells, in the development of diabetic nephropathy We then performed gene expression profiling analysis using data obtained from RNA-seq of glomerular cells of control(m/m), diabetic (db-/- 6-week-old) and diabetic nephropathy (db-/- 10-week-old with albuminuria) mice
2023-10-27 | GSE219268 | GEO
Project description:Podocyte injury in diabetic kidney disease contributes to the development of albuminuria and subsequent renal decline. Clinically, gastric bypass surgery is associated with reductions in albuminuria, and rodent studies demonstrate coherent improvements in renal histology. We aimed to investigate the mechanisms underpinning remission of albuminuria following gastric bypass focussing on podocyte injury. Firstly, we tracked the evolution of albuminuria and cognate evidence of histological and ultrastructural damage to the glomerulus in male Zucker Diabetic Fatty rats. Secondly, we examined the impact of gastric bypass in these rats, focussing on podocyte injury. Thirdly, we conducted a global transcriptomic study profiling the shift in the renal transcriptome in the Zucker Diabetic Fatty rats rat and its relevance to human disease. Lastly, we explored whether gastric bypass could reverse the changes seen in the disease associated transcriptome. Albuminuria in the Zucker Diabetic Fatty rat developed by 12 weeks of age. This was accompanied by glomerulomegaly, podocyte stress and ultrastructural evidence of podocyte dedifferentiation. When animals underwent gastric bypass at 12 weeks of age, marked reductions in albuminuria in association with normalisation of glomerular tuft size, attenuation of podocyte stress and improvements in podocyte foot process morphology were observed within 2 months of surgery. A characteristic disease associated gene expression signature was observed in the kidneys of Zucker Diabetic Fatty rats, with a core set of alterations conserved in global analysis of the human DKD transcriptome. Many of the shared gene expression alterations were reversed by gastric bypass. Reductions in podocyte injury represent a key mechanism underpinning the remission of albuminuria following gastric bypass.
2019-07-10 | GSE117085 | GEO
Project description:Glomerular diseases are the leading cause of chronic kidney diseases with pathomechanisms largely unclear. It is known that ANGPT2 regulates endothelial cell homeostasis and function via TEK/TIE2 and its deregulation causes endothelial damage. We found that ANGPT2 is upregulated in glomerular diseases and wondered whether it has any effect on glomerular podocytes and mesangial cells given that they have no or low TEK expression. We treated podocytes and mesangial cells in culture with ANGPT2 and found no overt cellular changes. RNA-seq analysis showed that gene expression was altered in both podocytes and mesangial cells and that the regulated genes in the two cell types were fundamentally different. GO and KEGG analyses showed that the two groups of regulated genes were enriched in distinct processes and pathways. These results suggest that ANGPT2 exerts effects on both podocytes and mesangial cells and that increased ANGPT2 may be involved in glomerular injury by affecting podocytes and mesangial cells in addition to endothelial cells.
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Project description:Chronic glucagon receptor activation induced by a long-acting glucagon analogue causes thickening of the parietal layer of Bowman’s capsule, causes mesangial area expansion, and formation of albuminuria. To dissect the molecular mechanism underlying these effects, RNA sequencing of kidney biopsies from female mice treated for eight weeks with either the long-acting glucagon analogue, NNC9204-0043, or PBS were performed
2023-12-01 | E-MTAB-12520 | biostudies-arrayexpress
Project description:Activation of JAK-STAT signaling has been implicated in the pathogenesis of diabetic kidney disease. An increased expression of JAK-STAT genes was found in kidney glomerular cells, including podocytes, in patients with early diabetic kidney disease. However, it is not known whether increased expression of JAK or STAT isoforms in glomerular cells can lead to worsening nephropathy in the setting of diabetes. Therefore, we overexpressed JAK2 mRNA specifically in glomerular podocytes of 129S6 mice to determine whether this change alone could worsen diabetic kidney disease. A 2-3 fold increase in glomerular JAK2 expression, an increase similar to that found in humans with early diabetic kidney disease, led to substantial and statistically significant increases in albuminuria, mesangial expansion, glomerulosclerosis, glomerular fibronectin accumulation, and glomerular basement membrane thickening, and a significant reduction in podocyte density in diabetic mice. Treatment with a specific JAK1/2 inhibitor for 2 weeks partly reversed the major phenotypic changes of diabetic kidney disease and specifically normalized expression of a number of downstream STAT3-dependent genes implicated in diabetic kidney disease progression. Thus, moderate increases in podocyte JAK2 expression at levels similar to those in patients with early diabetic kidney disease can lead directly to phenotypic and other alterations of progressive diabetic glomerulopathy. Hence, inhibition of these changes by treatment with a JAK1/2 inhibitor suggests that such treatment may help retard progression of early diabetic kidney disease in patients.
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Project description:The Chinese herbal granule Tangshen Formula (TSF) has been proven to decrease proteinuria and improve estimated glomerular filtration rate (eGFR) in diabetic kidney disease (DKD) patients with albuminuria. Nevertheless, little was known on the underlying mechanisms of TSF on treating DN. We used microarrays to detail to explore the target genes of TSF in the treatment of DN.
2017-01-25 | GSE90842 | GEO
Project description:The Wilms tumor-suppressor gene WT1, a key player in renal development, also has a crucial role in maintenance of the glomerulus in the mature kidney. However, molecular pathways orchestrated by WT1 in podocytes, where it is highly expressed, remain unknown. Their defects are thought to modify the cross-talk between podocytes and other glomerular cells and ultimately lead to glomerular sclerosis, as observed in diffuse mesangial sclerosis (DMS) a nephropathy associated with WT1 mutations. To identify podocyte WT1 targets, we generated a novel DMS mouse line, performed gene expression profiling in isolated glomeruli, and identified excellent candidates that may modify podocyte differentiation and growth factor signalling in glomeruli. Scel, encoding sciellin, a protein of the cornified envelope in the skin, and sulf1, encoding a 6-O endosulfatase, are shown to be expressed in wild type podocytes and to be strongly down-regulated in mutants. Co-expression of Wt1, Scel and Sulf1 was also found in a mesonephric cell line, and siRNA-mediated knockdown of WT1 decreased Scel and Sulf1 mRNAs and proteins. By ChIP we show that Scel and Sulf1 are direct WT1 targets. Cyp26a1, encoding an enzyme involved in the degradation of retinoic acid, is shown to be up-regulated in mutant podocytes. Cyp26a1 may play a role in the development of glomerular lesions but does not seem to be regulated by WT1. These results provide novel clues in our understanding of normal glomerular function and early events involved in glomerulosclerosis. Experiment Overall Design: Isolation of glomeruli from mutant (FVB-N4 Wt1+/R394W) and wild-type (FVB-N4 Wt1+/+) was performed after cardiac Dynabead perfusion. GeneChip analysis of glomeruli from 5 Wt1+/R394W mice and 5 Wt1+/+ littermates (N4-FVB) were performed independently. Animals were unweaned 27-day-old males. The Wt1+/R394W mice used were showing little albuminuria (<3 ug/ul on Coomassie blue stained SDS-PAGE gel) and no evidence of mesangial lesions by light microscopy.
2009-10-09 | E-GEOD-18358 | biostudies-arrayexpress
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