Translational research : the journal of laboratory and clinical medicine
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Diabetic nephropathy remains a common cause of end-stage renal failure and its associated mortality around the world. Sphingosine 1-phosphate (S1P) is a multifunctional lipid mediator and binds to HDL via apolipoprotein M (ApoM). Since HDL has been reported to be epidemiologically associated with kidney disease, we attempted to investigate the involvement of the ApoM/S1P axis in the pathogenesis/progression of diabetic nephropathy. ⋯ ApoM/S1P axis attenuated activation of the Smad3 pathway, while augmented eNOS phosphorylation through the S1P1 pathway. Moreover, ApoM/S1P increased the SIRT1 protein levels and enhanced mitochondrial functions by increasing the S1P content of the cell membrane, which might cause selective activation of S1P1. ApoM might be a useful biomarker for predicting the progression of diabetic nephropathy, and the ApoM/S1P-S1P1 axis might serve as a novel therapeutic target for preventing the development/progression of diabetic nephropathy.
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The purinergic receptor P2X7 has been established as an important mediator of inflammation and participates in a variety of cardiovascular diseases including atherosclerosis, however, its role in abdominal aortic aneurysms (AAA) remains unclear. In this study, we demonstrate that P2X7 plays essential roles in AAA development via modulating macrophage pyroptosis and inflammation. P2X7 is highly expressed in human AAA specimen, as well as in experimental murine AAA lesions (both CaCl2- and Angiotensin II-induced AAA models), and it mainly confines in macrophages. ⋯ Consequently, the N-terminal fragment of GSDMD forms pores on the cell membrane, leading to macrophage pyroptosis and release of the pro-inflammatory factor IL-1β. The resulting vascular inflammation further leads to the upregulation of MMP and ROS, thereby promoting AAA development. In summary, these data identify P2X7-mediated macrophage pyroptosis signaling pathway as a novel contributory mechanism of AAA formation.
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CRISPR/Cas9-mediated A4GALT suppression rescues Fabry disease phenotypes in a kidney organoid model.
The objective of this study was to investigate whether CRISPR/Cas9-mediated suppression of A4GALT could rescue phenotype of Fabry disease nephropathy (FDN) using human induced pluripotent stem cells (hiPSCs) derived kidney organoid system. We generated FDN patient-derived hiPSC (CMC-Fb-002) and FD-specific hiPSCs (GLA-KO) by knock-out (KO) of GLA in wild-type (WT) hiPSCs using CRISPR/Cas9. We then performed A4GALT KO in both CMC-Fb-002 and GLA-KO to make Fb-002-A4GALT-KO and GLA/A4GALT-KO, respectively. ⋯ Such increases were rescued in GLA/A4GALT-KO or Fb-002-A4GALT-KO organoids. CRISPR/Cas9 mediated suppression of A4GALT could rescue FDN phenotype. Hence, it can be proposed as a therapeutic approach to treat FDN.
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Fabry disease (FD) is an X-linked lysosomal rare disease due to a deficiency of α-galactosidase A activity. The accumulation of glycosphingolipids mainly affects the kidney, heart, and central nervous system, considerably reducing life expectancy. Although the accumulation of undegraded substrate is considered the primary cause of FD, it is established that secondary dysfunctions at the cellular, tissue, and organ levels ultimately give rise to the clinical phenotype. ⋯ Our findings highlight the pro-inflammatory cytokines' involvement in FD pathogenesis along with extracellular matrix remodeling. The study shows a tissue-wide metabolic remodeling connection to plasma proteomics in FD. These results will facilitate further studies to understand the molecular mechanisms in FD to pave the way for better diagnostics and therapeutics.
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Targeting Mutant Dicer Tumorigenesis in Pleuropulmonary Blastoma via Inhibition of RNA Polymerase I.
DICER1 mutations predispose to increased risk for various cancers, particularly pleuropulmonary blastoma (PPB), the commonest lung malignancy of childhood. There is a paucity of directly actionable molecular targets as these tumors are driven by loss-of-function mutations of DICER1. Therapeutic development for PPB is further limited by a lack of biologically and physiologically-representative disease models. ⋯ In PDX tumors, CX-5461 significantly reduced H3K9 di-methylation and increased nuclear p53 expression, within 24 hours' exposure. Following treatment at the maximum tolerated dosing regimen (12 doses, 30 mg/kg), tumors were smaller and less hemorrhagic than controls, with significantly decreased cellular proliferation, and increased apoptosis. As demonstrated in a novel intrathoracic tumor model of PPB, Pol I inhibition with CX-5461 could be a tolerable and clinically-feasible therapeutic strategy for mutant Dicer tumors, inducing antitumor effects by decreasing H3K9 methylation and enhancing p53-mediated apoptosis.