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Endothelial Kallikrein-Related Peptidase 8 Promotes Diabetic Nephropathy via Reducing SDC4 Expression and Enhancing LIF Release

ABSTRACT: Endothelial Kallikrein-Related Peptidase 8 Promotes Diabetic Nephropathy via Reducing SDC4 Expression and Enhancing LIF Release

PROVIDER: PRJNA1073260 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27868911_1.fastq.gz	Fastqsanger.gz
	SRR27868911_2.fastq.gz	Fastqsanger.gz
	SRR27868912_1.fastq.gz	Fastqsanger.gz
	SRR27868912_2.fastq.gz	Fastqsanger.gz
	SRR27868913_1.fastq.gz	Fastqsanger.gz

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Endothelial Kallikrein-Related Peptidase 8 Promotes Diabetic Nephropathy via Reducing SDC4 Expression and Enhancing LIF Release

Project description:The molecular mechanisms underlying diabetic nephropathy (DN) are poorly defined. We sought to investigate the roles of kallikrein-related peptidases (KLKs) in DN pathogenesis. Screening of renal tissue from diabetic mice revealed KLK8 as the most highly induced gene in KLK family. KLK8 expression was greater in glomerular endothelial cells (GECs) than other glomerular cells in DN patients and diabetic mice. The rats with KLK8 overexpression exhibited proteinuria, reduced glomerular filtration rate (GFR), and mesangial expansion, podocytopenia, glomerulosclerosis and interstitial fibrosis in renal tissues. In contrast, global KLK8 deficiency reversed streptozotocin-induced hallmark of DN features including proteinuria, reduced GFR, glomerular hypertrophy, glycocalyx loss in GECs, podocytopenia, leukocyte infiltration, glomerulosclerosis, and interstitial fibrosis in mice. Moreover, endothelial KLK8 ablation also blocked streptozotocin-induced hallmark of DN features. Mechanically, elevated KLK8 in GECs promoted endothelial hyperpermeability, glycocalyx injury, and monocyte recruitment and adhesion through downregulation and shedding of syndecan-4 (SDC4). KLK8 upregulation in GECs stimulated mesangial cell proliferation and activation via increasing leukemia inhibitory factor (LIF) release. Moreover, circulatory KLK8 levels correlated positively with LIF and SDC4 in diabetic nephropathy patients. Our study identifies KLK8 as a novel driver of DN development and progress and highlight potential therapeutic strategies targeting KLK8 for DN.

2024-12-31 | GSE255028 | GEO

Involvement of kallikrein-related peptidase 6 in epithelial to mesenchymal transition induced by ΔNp63 downregulation in oral squamous cell carcinoma through activation of protease activated receptors

Project description:Recent studies showed epithelial-mesenchymal transition (EMT) is involved in cancer progression. Though we revealed that downregulation of ΔNp63 in oral squamous cell carcinoma (OSCC) induces EMT, the detailed molecular mechanisms remain to be elucidated. DNA microarray analyses were thus performed by using OSCC cell line overexpressing ΔNp63 to examine the genes associated with EMT. The results revealed that kallikrein related peptidase 6 (KLK6) was most upregulated in the OSCC cells overexpressing ΔNp63.

2018-04-01 | GSE90064 | GEO

Integration of two in-depth proteomics approaches determines the high grade serous ovarian cancer-associated kallikrein-related peptidase 7 (KLK7) degradome

Project description:Kallikrein-related peptidase 7 (KLK7) is a serine peptidase that is over-produced in the most lethal form of ovarian cancer, called high grade serous ovarian cancer (HGSOC). To determine its underlying molecular mechanism of action, a comprehensive analysis of KLK7 degradome in the SKOV-3 cell-secreted proteins was performed using two complementary proteomic approaches, quantitative PROtein Topography and Migration Analysis Platform (qPROTOMAP) and Terminal Amine Isotopic Labelling of Substrates (TAILS).

2019-02-15 | PXD003812 | Pride

Integration of two in-depth proteomics approaches determines the high grade serous ovarian cancer-associated kallikrein-related peptidase 7 (KLK7) degradome

Project description:Kallikrein-related peptidase 7 (KLK7) is a serine peptidase that is over-produced in the most lethal form of ovarian cancer, called high grade serous ovarian cancer (HGSOC). To determine its underlying molecular mechanism of action, a comprehensive analysis of KLK7 degradome in the OVMZ-6 cell-secreted proteins was performed using two complementary proteomic approaches, quantitative PROtein Topography and Migration Analysis Platform (qPROTOMAP) and Terminal Amine Isotopic Labelling of Substrates (TAILS).

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Integration of two in-depth proteomics approaches determines the high grade serous ovarian cancer-associated kallikrein-related peptidase 7 (KLK7) degradome

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Secretory Leukocyte Peptidase Inhibitor (SLPI) is a Novel Predictor of Tubulointerstitial Injury and Renal Outcome in Patients with Diabetic Nephropathy

Project description:Tubulointerstitial injury plays an important role in diabetic nephropathy (DN) progression; however, no reliable urinary molecule has been used to predict tubulointerstitial injury and renal outcome of DN clinically. In this study, based on tubulointerstitial transcriptome, we identified secretory leukocyte peptidase inhibitor (SLPI) as the molecule associated with renal fibrosis and prognosis of DN. In tubular cells, high glucose could upregulate SLPI, which bound with β-catenin and GSK-3β reciprocally, abolished the interaction between β-catenin and GSK-3β, diminished GSK-3β-regulated β-catenin phosphorylation and the subsequent ubiquitination and degradation, thus led to β-catenin signaling activation and renal fibrosis. Db/db mice injected with adenovirus carrying Slpi-3xflag-GFP (Ad-Slpi-GFP) developed β-catenin signaling activation in the proximal tubule, worse albuminuria and tubulointerstitial fibrosis. Conversely, Slpi knockout (KO) mice with STZ-induced DN developed less albuminuria, tubulointerstitial fibrosis and β-catenin signaling activation. Furthermore, clinical studies showed that urinary SLPI protein level (uSLPI/Cr) had significant correlation with intrarenal SLPI mRNA and interstitial fibrosis. In an independent prospective cohort enrolled 711 patients with biopsy proven DN, uSLPI/Cr level was significantly associated with eGFR slope and improved the prediction value of renal outcome. Together, our study identified SLPI as a novel critical regulator for the progression of tubulointerstitial injury, which may be used as an independent risk predictor of DN progression.

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Project description:Leukemia Inhibitory Factor (LIF) plays an essential role in the maintenance of pluripotency of mouse embryonic stem cells (mESCs). LIF withdrawal induces mESC differentiation. To define noval pluripotent factors downstream of LIF signaling, cDNA microarray was used and seveal well-known pluripotent genes were found to respond to LIF withdrawal, including Klf4, Esrrb, Tbx3, and Prdm14.

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Project description:In order to identify the genes involved in LIF/gp130 self-renewal response, we analyzed the transcriptome of Gs2 ES cells induced to differentiate upon LIF withdrawal for 16h, 24h and 48h (LIF16, LIF24 and LIF48 respectively)and compared them to that of undifferentiated ES Gs2 cells continuously maintained in the presence of LIF. Since this cell line also carry a tetracycline regulatable dominant negative form of Stat3 (Stat3F, all the experiment was done in the presence of Tetracycline (tet ON) to avoid Stat3F expression. Keywords: time-course

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Identification of RNA binding proteins that interact with AU-rich elements of Lif 3`UTR

Project description:Leukemia inhibitory factor (LIF) is an important endogenous factor for photoreceptor protection. Lif is known to be upregulated both in induced and inherited disease models of photoreceptor degeneration only in a subset of Muller cells. Since Lif is induced in Muller cells in response to photoreceptor injury, we studied its regulation in Muller cells. We have recently identified several AU-rich elements (AREs) within the 3′ untranslated region (UTR) of Lif . We also showed that as a result of these elements Lif encodes a highly unstable mRNA. mRNAs containing AREs in the 3`UTR undergo rapid ARE-mediated mRNA decay in the cytoplasm which is mediated by the RNA–binding proteins. In order to identify the RNA-binding proteins that are involved in the regulation of Lif transcripts, we will use the biotin-labelled RNA. By using this methodology, we will isolate the related RNA binding proteins. We plan to analyze the isolated proteins by mass spectrometry, and compare the mass spectrometry results of different regions with or without AREs . Once we identify the specific proteins that bind only to AREs, we will do the functional characterization of these proteins by cotransfecting the constructs with AREs and the siRNA that inhibits the expression of related RNA binding protein.

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