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Next Generation Sequencing identifies Cdh11 and Mrc1 as novel translational biomarkers of kidney fibrosis

ABSTRACT: Chronic kidney disease (CKD) is the gradual, asymptomatic loss of kidney function and current tests only identify it when significant loss has already happened. Using RNA sequencing in a mouse model of folic acid (FA) induced nephropathy, here we report the identification of 10 genes that track kidney fibrosis development, the common pathological finding in CKD patients. The gene expression of all 10 candidates was confirmed to be significantly high (~ 10-150 fold) in three well-established and mechanistically distinct mouse models of kidney fibrosis. Protein expression was also high in the FA model as well as patients with biopsy-proven kidney fibrosis. The specificity of these 10 candidates for kidney fibrosis was demonstrated by showing a very modest (~ 2-5 fold) increase in the mouse models of acute kidney injury as well as following liver fibrosis in mice and humans. Using targeted selected reaction monitoring mass spectrometry (SRM-MS) we found that 3 out of 10, cadherin 11 (CDH11), mannose receptor C1 (MRC1), phospholipid transfer protein (PLTP), are detectable in human urine. Furthermore, the levels of CDH11 and MRC1 are able to distinguish patients with chronic kidney disease from healthy individuals (n = 78, p<0.01). In summary, we report the identification of CDH11 and MRC1 as novel non-invasive biomarkers of CKD.

ORGANISM(S): Mus musculus

PROVIDER: GSE65267 | GEO | 2015/10/23

SECONDARY ACCESSION(S): PRJNA273550

REPOSITORIES: GEO

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Next Generation Sequencing identifies Cdh11 and Mrc1 as novel translational biomarkers of kidney fibrosis

Project description:Chronic kidney disease (CKD) is the gradual, asymptomatic loss of kidney function and current tests only identify it when significant loss has already happened. Using RNA sequencing in a mouse model of folic acid (FA) induced nephropathy, here we report the identification of 10 genes that track kidney fibrosis development, the common pathological finding in CKD patients. The gene expression of all 10 candidates was confirmed to be significantly high (~ 10-150 fold) in three well-established and mechanistically distinct mouse models of kidney fibrosis. Protein expression was also high in the FA model as well as patients with biopsy-proven kidney fibrosis. The specificity of these 10 candidates for kidney fibrosis was demonstrated by showing a very modest (~ 2-5 fold) increase in the mouse models of acute kidney injury as well as following liver fibrosis in mice and humans. Using targeted selected reaction monitoring mass spectrometry (SRM-MS) we found that 3 out of 10, cadherin 11 (CDH11), mannose receptor C1 (MRC1), phospholipid transfer protein (PLTP), are detectable in human urine. Furthermore, the levels of CDH11 and MRC1 are able to distinguish patients with chronic kidney disease from healthy individuals (n = 78, p<0.01). In summary, we report the identification of CDH11 and MRC1 as novel non-invasive biomarkers of CKD. mRNA sequencing of mouse kidney before and at various time points (1,2,3,7 & 14 days) after intraperitoneal treatment with folic acid.

2015-10-23 | E-GEOD-65267 | biostudies-arrayexpress

Acyloxyacyl Hydrolase Protects against Kidney Injury via Inhibition of Tubular CD74-Macrophage Crosstalk

Project description:Renal fibrosis is the common pathway in the progression of chronic kidney disease (CKD). Acyloxyacyl hydrolase (AOAH) is expressed in various phagocytes and is highly expressed in proximal tubular epithelial cells (PTECs). Research shows that AOAH plays a critical role in infections and chronic inflammatory diseases, although its role in kidney injury is unknown. Here, we found that AOAH deletion led to exacerbated kidney injury and fibrosis after folic acid (FA) administration, which was reversed by overexpression of Aoah in kidneys. ScRNA-seq revealed that Aoah-/- mice exhibited increased subpopulation of CD74+ PTECs, though the percentage of total PTECs were decreased compared to WT mice after FA treatment. Additionally, exacerbated kidney injury and fibrosis seen in Aoah-/- mice was attenuated via administration of methyl ester of (S, R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid (ISO-1), an inhibitor of macrophage inhibition factor (MIF) and CD74 binding. Finally, AOAH expression was found positively correlated with estimated glomerular filtration rate while negatively correlated with the degree of renal fibrosis in kidneys of CKD patients. Thus, our work indicates that AOAH protects against kidney injury and fibrosis by inhibiting renal tubular epithelial cells CD74 signaling pathways. Targeting kidney AOAH represents a promising strategy to prevent renal fibrosis progression.

2023-12-01 | GSE234090 | GEO

Mus musculus

Project description:Next Generation Sequencing identifies Cdh11 and Mrc1 as novel translational biomarkers of kidney fibrosis

| PRJNA273550 | ENA

Iron and kidney macrophages in CKD

Project description:Systemic iron metabolism is disrupted in chronic kidney disease (CKD). However, little is known about local kidney iron homeostasis and its role in kidney fibrosis. Kidney-specific effects of iron therapy in CKD also remain elusive. Here, we elucidate the role of macrophage iron status in kidney fibrosis and demonstrate that it is a potential therapeutic target. In CKD, kidney macrophages exhibited depletion of labile iron pool (LIP) and induction of transferrin receptor 1, indicating intracellular iron deficiency. Low LIP in kidney macrophages was associated with their defective antioxidant response and proinflammatory polarization. Repletion of LIP in kidney macrophages through knockout of ferritin heavy chain (Fth1) reduced oxidative stress and mitigated fibrosis. Similar to Fth1 knockout, iron dextran therapy, through replenishing macrophage LIP, reduced oxidative stress, decreased the production of proinflammatory cytokines, and alleviated kidney fibrosis. Interestingly, iron markedly decreased TGF-β expression and suppressed TGF-β–driven fibrotic response of macrophages. Iron dextran therapy and FtH suppression had an additive protective effect against fibrosis. Adoptive transfer of iron-loaded macrophages alleviated kidney fibrosis, validating the protective effect of iron-replete macrophages in CKD. Thus, targeting intracellular iron deficiency of kidney macrophages in CKD can serve as a therapeutic opportunity to mitigate disease progression.

2023-02-01 | GSE221598 | GEO

Exploring new pathways involved during experimental renal fibrogenesis in the Unilateral Ureteral Obstruction

Project description:Chronic kidney disease (CKD) is a burden for Public Health and concerns millions of individuals worldwide. Independently of the cause, CKD is secondary to the replacement of functional renal tissue by extra-cellular matrix proteins (i.e fibrosis) that progressively impairs kidney function. The pathophysiological pathways that control the development of renal fibrosis are common to most of the nephropathies involving native kidneys or kidney grafts. Unfortunately, very few treatments are available to stop renal fibrosis and most of the therapeutic strategies are often barely able to slow down the progression of fibrogenesis in native kidneys. Therefore, it is mandatory to discover new therapeutic pathways to stop renal fibrosis. Our objective is to study new pathways involved in renal fibrosis. We thus decided to use the model of Unilateral Ureteral renal Obstruction in mice, a fast and reproducible experimental model of renal fibrosis. We studied renal fibrosis using experimental model of ureteral unilateral obstruction in mice, which was performed by complete ligation of the left ureter. The control lateral right kidney served as internal control.

2013-02-10 | E-GEOD-38117 | biostudies-arrayexpress

Muscle fibrosis in chronic kidney disease

Project description:Patients with chronic kidney disease (CKD) are at markedly increased risk of disability, hospitalization, and death. Impaired physical function, which is common in CKD, is a major risk factor for these poor outcomes. CKD patients perform substantially below age-predicted norms on a variety of clinically relevant physical performance tests. Altered muscle physiology is an important cause of these functional deficits. We recently described skeletal muscle fibrosis in the vastus lateralis muscle of patients with severely impaired kidney function. Greater severity of fibrosis was associated with lower leg extension strength and reduced endurance capacity, suggesting that muscle fibrosis in CKD patients is functionally significant. An important unanswered question is whether muscle fibrosis in CKD is a slowly progressive process beginning with early loss of kidney function, or a complication observed only with severe disease. Here, we examined the associations of estimated glomerular filtration rate (a measure of kidney function) with measures of fibrosis across a broad range of kidney function, and tested the effect of receiving treatment with dialysis. We also integrated muscle transcriptomic analyses to provide further insight into this novel aspect of muscle pathology in CKD.

2021-03-01 | GSE157712 | GEO

Tissue Transcriptome Driven Identification of Epidermal Growth Factor as a Chronic Kidney Disease Biomarker

Project description:We identified EGF as the top candidates predicting kidney function through an intrarenal transcriptome-driven approach, and demonstrated it is an independent risk predictor of CKD progression and can significantly improve prediction of renal outcome by established clinical parameters in diverse populations with CKD from a wide spectrum of causes and stages Chronic Kidney Disease, Lupus nephritis, Focal and Segmental Glomerulosclerosis, Nephropathies, Membranous Glomerulonephritis. This dataset is part of the TransQST collection.

2015-12-14 | E-GEOD-69438 | biostudies-arrayexpress

Mrc1 marks early-firing origins and coordinates timing and efficiency of initiation in fission yeast

Project description:How early- and late-firing origins are selected on eukaryotic chromosomes is largely unknown. Here we show that Mrc1, a conserved factor required for stabilization of stalled replication forks, selectively binds to the early-firing origins in a manner independent of Cdc45 and Hsk1 kinase in fission yeast. In mrc1∆ (and in swi1∆ to some extent), efficiency of firing is stimulated and its timing is advanced selectively at those origins that are normally bound by Mrc1. In contrast, the late or inefficient origins which are not bound by Mrc1 are not activated in mrc1∆. The enhanced firing and precocious Cdc45 loading at Mrc1-bound early-firing origins are not observed in a checkpoint mutant of mrc1, suggesting that non-checkpoint function is involved in maintaining the normal program of early-firing origins. We propose that pre-firing binding of Mrc1 is an important marker of early-firing origins which are precociously activated by the absence this protein. Mrc1 binding profiles at G1/S boundary or early S-phase in wild type vs hsk1-89 mutant.

2011-03-26 | GSE28182 | GEO

Whole transcriptome analysis of human kidney cells after treatment with or without phosphoramidon

Project description:The mechanism of autophagy can be triggered by phosphoramidon to ameliorate kidney fibrosis and inflammation. The precise targets of fibrosis and inflammation in chronic kidney disease (CKD) need further investigation. The purpose of this project is to development of potential therapeutic drugs for CKD treatment. The therapeutic targets might be identified from cellular signaling induced by phosphoramidon in the human kidney proximal tubular epithelial cell line (HK-2 cells).

2023-08-01 | GSE203181 | GEO

Checkpoint-independent Regulation of Origin Firing by Mrc1 through Interaction with Hsk1 kinase

Project description:Mrc1 is a conserved checkpoint mediator protein that transduces replication-stress signal to downstream effector kinase. Loss of mrc1 checkpoint activity results in aberrant activation of late/dormant origins in the presence of hydroxyurea. Mrc1 was also suggested to regulate orders of early-origin firing in a checkpoint-independent manner, but its mechanism was unknown. Here we identify HBS (Hsk1 Bypass Segment) on Mrc1. ∆HBS does not suppress late/dormant origin firing in the presence of hydroxyurea but causes precocious and enhanced activation of weak early-firing origins during normal S-phase progression, and bypasses the requirement of Hsk1 for growth. This may be caused by disruption of intramolecular binding between HBS and NTHBS (N-terminal-Target-of-HBS). Hsk1 binds to Mrc1 through HBS and phosphorylates a segment adjacent to NTHBS, disrupting intramolecular interaction. We propose that Mrc1 exerts “brake” on initiation (through intra-molecular interaction) and this brake can be released (upon loss of intra-molecular interaction) by either Hsk1-mediated phosphorylation of Mrc1 or deletion of HBS (or phosphomimic mutation) which can bypass the function of Hsk1 for growth. The “brake” mechanism may explain the checkpoint-independent regulation of early origin firing in fission yeast.

2017-01-06 | GSE93178 | GEO

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