YSHS activates PPAR signaling pathway to protect adenine-induced kidney injury
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus
SUBMITTER: 
Rong Zeng
PROVIDER: PXD072537 | iProX | Tue Dec 30 00:00:00 GMT 2025
REPOSITORIES: iProX
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Project description:Kidney fibrosis an important determinant of clinical outcomes in individuals with chronic kidney disease (CKD). The stoichiometric ratio of collagens in renal scar tissue differs from that of ECM of healthy kidneys but the functional importance of altered collagen types injured kidneys remains unclear. Using population studies and multiple independent clinical datasets, we show that circulating protein and renal mRNA amounts of Col5a1 exhibited associations with kidney disease and incident CKD risk. Using murine models of tubulo-interstitial kidney injury, we show that Col V regulates the degree of post injury fibrosis and renal function. We demonstrated that mice with conditionally knocked out Col5a1 (Col5a1CKO ) exhibited decreased renal function and greater renal fibrosis after kidney injury . Renal fibroblasts in Col5a1CKO animals upregulated vβ3 integrin. Inhibition of vβ3 signaling with a small molecule, cilengitide, rescued post-injury renal function in Col5a1 CKO animals. Using the hybrid mouse diversity panel (HMDP) that comprises 100 diverse inbred strains of mice, we observed that the ratio of expression of Col5a1 after injury compared to healthy animals exhibited genetic variation . Strains with low Col5a1 ratios exhibited worse renal function compared to animals that had higher ratios . Col5a1 expression in peripheral blood mononuclear cells after injury compared to uninjured animals to identify Col5a1-non responder strains, we demonstrate that cilengitide can significan tly rescue kidney function in non-responder strains . Overall we found that Col V regulates renal function and fibrosis after kidney injury. These data suggest the feasibility of precision medicine approaches for targeting pathways downstream of Col5a1 to promote kidney repair.
2025-03-17 | GSE290663 | GEO
Project description:Kidney fibrosis an important determinant of clinical outcomes in individuals with chronic kidney disease (CKD). The stoichiometric ratio of collagens in renal scar tissue differs from that of ECM of healthy kidneys but the functional importance of altered collagen types injured kidneys remains unclear. Using population studies and multiple independent clinical datasets, we show that circulating protein and renal mRNA amounts of Col5a1 exhibited associations with kidney disease and incident CKD risk. Using murine models of tubulo-interstitial kidney injury, we show that Col V regulates the degree of post injury fibrosis and renal function. We demonstrated that mice with conditionally knocked out Col5a1 (Col5a1CKO ) exhibited decreased renal function and greater renal fibrosis after kidney injury . Renal fibroblasts in Col5a1CKO animals upregulated vβ3 integrin. Inhibition of vβ3 signaling with a small molecule, cilengitide, rescued post-injury renal function in Col5a1 CKO animals. Using the hybrid mouse diversity panel (HMDP) that comprises 100 diverse inbred strains of mice, we observed that the ratio of expression of Col5a1 after injury compared to healthy animals exhibited genetic variation . Strains with low Col5a1 ratios exhibited worse renal function compared to animals that had higher ratios . Col5a1 expression in peripheral blood mononuclear cells after injury compared to uninjured animals to identify Col5a1-non responder strains, we demonstrate that cilengitide can significan tly rescue kidney function in non-responder strains . Overall we found that Col V regulates renal function and fibrosis after kidney injury. These data suggest the feasibility of precision medicine approaches for targeting pathways downstream of Col5a1 to promote kidney repair.
2025-03-17 | GSE290664 | GEO
Project description:Tissue inhibitors of metalloproteinases (TIMP) are endogenous inhibitors of matrix metalloproteinases (MMP). While TIMP2 and TIMP3 inhibit MMPs, TIMP3 also inhibits activation of pro-MMP2 whereas TIMP2 promotes it. Here we assessed the differential role of TIMP2 and TIMP3 in renal injury using the unilateral ureteral obstruction model. Gene microarray assay showed that post-obstruction, the lack of TIMP3 had a greater impact on gene expression of intermediate, late injury- and repair-induced transcripts, kidney selective transcripts and solute carriers. Renal injury in TIMP3-/-, but not in TIMP2-/- mice increased expression of collagen type I/III, connective tissue growth factor, transforming growth factor-β and the downstream Smad2/3 pathway. Interestingly, ureteral obstruction markedly increased MMP2 activation in the kidneys of TIMP3-/- mice which was completely blocked in the kidneys of TIMP2-/- mice. These changes are consistent with enhanced renal tubulointerstitial fibrosis in TIMP3-/- and its reduction in TIMP2-/- mice. The activity of tumor necrosis factor-α converting enzyme, caspase-3 and mitogen activated kinases were elevated in the kidneys of TIMP3-/- but not TIMP2-/- mice, suggesting enhanced activation of apoptotic and pathological signaling pathways only in the obstructed kidney of TIMP3-/- mice. Thus, TIMP2 and TIMP3 play differential and contrasting roles in renal injury, TIMP3 protects from damage whereas TIMP2 promotes injury through MMP2 activation. Kidneys from the wild type (WT), TIMP2-/- and TIMP3-/- mice undergoing sham or unilateral ureteral obstruction (UUO) procedures
2013-07-01 | E-GEOD-42303 | biostudies-arrayexpress
Project description:Background The mysterious chronic kidney disease is multifactorial causes. One of the risk factors is leptospirosis, a re-emerging infectious disease caused by Leptospira spp., for endemic leptospirosis tend to coincide with high-incidence regions of chronic kidney disease of unknown etiology. This study aims to investigate the role of leptospirosis as an emerging culprit in which chronic subclinical kidney injury, may predispose to progressive kidney disease when superimposed on secondary nephrotoxic injury. Methods Adenine-induced renal injury in chronic leptospira-infected C57/BL6 mice were studied for evaluating the renal function, histology and gene expression changes. We employed RNA sequencing-based renal transcriptome to investigate pathogenic pathways associated with secondary nephrotoxic injury in chronic kidney injury due to leptospirosis. Results The severity of kidney lesions was increased and the expression of immune/inflammation/fibrosis genes were significantly up-regulated in either low-dose (0.1%) and high-dose (0.2%) adenine-induced renal injury superimposed on infected mice. Whole renal transcriptome analysis reveals that the substantial amplification of the tremendous amount of expressed genes and fibrosis-related pathways was found in adenine-induced kidney injury add-on to leptospira-infected mice which correlated with kidney dysfunction and fibrosis compared to infection or adenine itself. A total of 41 differentially expressed genes associated with fibrosis were identified in infected mice fed with adenine, suggesting that these potential genes contributed to aggravated renal progression occurred in adenine-fed chronic leptospira-infected mice. Conclusions In summary, this study indicates that chronic subclinical kidney infection when exposed to different degree of secondary nephrotoxic injury may predispose to exacerbated and progressive chronic kidney disease.
2021-04-05 | GSE150641 | GEO
Project description:TLR4 deficiency attenuates kidney injury after ischemic reperfusion as measured by both renal function and morphology. To better understand the role of TLR4 during the acute kidney injury, we used DNA microarray to identify genes that were differentially expressed on kidneys in wildtype B10 mice and TLR4 null mice during the early stage of injury. A murine ischemic reperfusion injury model was established. After right nephrectomy, the left pedicle was clamped for 23min followed by 4hr reperfusion. Sham mice were used as controls. 6 WT males and 6 TLR4 null males were included with 3 ischemic and 3 shams in each group.
2012-08-15 | E-GEOD-34351 | biostudies-arrayexpress
Project description:TLR4 deficiency attenuates kidney injury after ischemic reperfusion as measured by both renal function and morphology. To better understand the role of TLR4 during the acute kidney injury, we used DNA microarray to identify genes that were differentially expressed on kidneys in wildtype B10 mice and TLR4 null mice during the early stage of injury.
2012-08-15 | GSE34351 | GEO
Project description:Renal ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI) and presents significant challenges during kidney transplantation. Due to the detrimental effects of IRI on kidney function and the lack of effective intervention strategies, we conduct a multi-omics study on surgically induced mouse IRI, revealing a modulatory role for the metabolite S-adenosylmethionine (SAM) in AKI development. Our metabolic analysis of clinical samples establishes a link between various AKI conditions and marked elevations in serum SAM, underlying its potential as a biomarker for diagnosis. Furthermore, we find that short-term dietary methionine deprivation, which reduces circulating methionine and kidney SAM levels, effectively enhances renal resilience against IRI. In vivo isotopic tracing demonstrates that this diet preconditions kidney metabolic programs, enhancing glucose and fatty acid oxidation in preparation for IRI. Particularly, the activation of pyruvate dehydrogenase, which produces acetyl-CoA to fuel the tricarboxylic acid (TCA) cycle, highlights an energy-efficient strategy of glucose metabolism that is essential for the protective effects of dietary methionine deprivation.
2025-12-06 | PXD058530 | Pride
Project description:Protein L-isoaspartyl/D-aspartyl Methyltransferase (PCMT1) plays a pivotal role in repairing a spontaneous post-translational modification (PTM) of L-isoaspartyl residues resulted from asparagine deamidation or aspartate isomerization. This PTM is particularly important for extracellular matrix (ECM) proteins because their low turnover rate and are susceptible to factors that could accelerate such modification. Therefore, it becomes imperative to comprehensively investigate the impact of PCMT1 on ECM homeostasis and its associated pathological alterations. In this study, we revealed that secreted PCMT1 repairs the isoaspartyl residues of the TGFBR2 protein on the cell membrane to suppress TGF-β1/Smad pathway. Through this novel PTM regulation, PCMT1 played essential roles in combating renal fibrosis, as lack of PCMT1 worsened tubular injury, collagen deposition, myofibroblast activation, and macrophage infiltration in total kidney and tubular contexts in a mouse model of chronic kidney disease. Moreover, PCMT1 level decreased in fibrotic kidney tissues and inversely related to kidney function in mice and in humans. Our study highlights the important function of PCMT1 in modifying proteins in the extracellular space and identified a novel role of PCMT1 in regulating TGF-β1 pathway in renal fibrosis. This study holds the potential of innovative therapeutic avenue for the mitigation of renal fibrosis.
2025-03-18 | PXD047057 | Pride
Project description:Background: Low-level tragus stimulation (LL-TS) can reduce acute renal injury in sepsis and improve survival rates. However, the underlying molecular mechanisms remains unknown. Renal macrophages that contributed to AKI in sepsis under low-level tragus stimulation were characterized. Methods: Mice were randomly assigned to five groups following diverse treatments: Control, Sham, Sepsis, LL-TS + sepsis, and LL-TS + sepsis + Methyllycaconitine citrate (MLA). Blood creatinine testing and hematoxylin and eosin (HE) staining were used to assess kidney injury. Single-cell RNA sequencing were used to profile renal macrophages from CD45+ cells in mouse kidney. Western blot, immunofluorescence and HE staining were performed to verify the level of the alpha7 nicotinic acetylcholine receptor (α7nAChR) or interleukin-1β expression in kidney. Results: HE staining and blood creatinine testing of renal tissue indicated that LL-TS alleviated renal injury in mice with sepsis-associated acute kidney injury (AKI). A map of the renal cellular landscape was generated to identify macrophages that contributed to AKI in sepsis under LL-TS. Pseudo-timing analysis showed that LL-TS played an anti-inflammatory role by promoting renal monocyte conversion into M2 macrophages. Moreover, LL-TS significantly increased α7nAChR expression and decreased interleukin-1β expression in renal tissues. Conclusions: LL-TS alleviated sepsis-associated AKI by increasing α7nAChR expression and M2 macrophage polarization which promotes the anti-inflammatory process in sepsis. The results suggests that LL-TS may serve as a potential therapeutic strategy for sepsis-induced kidney dysfunction, ultimately improving patient outcomes.
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Project description:We recently developed a new model of renal agenesis [i.e., the heterogeneous stock derived model of unilateral renal agenesis, (HSRA)]. The HSRA model consistently exhibits unilateral renal agenesis ranging from 50-75% in each generation and is characterized by low nephron number, early kidney hypertrophy, and an inherent susceptibility to develop significant kidney injury and decline in renal function with age. Whole transcriptome analysis was evaluated at month 1 to identify early changes in genes/networks that may be involved in increased susceptibility of HSRA-S to develop kidney injury in the long-term. An n=4 per group (independent samples) were evaluated for HSRA-S (congenital solitary kidney) and HSRA-C (two-kidney). HSRA-C (two-kidney) samples were set as the control.
2014-10-07 | E-GEOD-62092 | biostudies-arrayexpress