Adrenergic receptor signaling induced by Klf15, a regulator of regeneration enhancer, promotes kidney reconstruction

Suzuki, Naoki; Kanai, Akinori; Suzuki, Yutaka; Ogino, Hitoshi; Ochi, Hiroki

doi:10.1073/pnas.2204338119

Cited by 10 publications

(8 citation statements)

References 44 publications

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“…Interestingly, MZsap130a mutants show a decrease in adrenergic signaling genes bcl2b, camk2d2, adcy3a, actc2, and gna15.1, implicating SAP130 is involved in mitochondrial biology (97). Evidence for adrenergic signaling being epigenetically regulated and interacting with troponin T of the sarcomere could further suggest sap130a's involvement in this metabolic process required for CM maturation (98,99,100). Further annotation of MZsap130a mutant hearts identified the same genes involved in metabolism and mitochondria to be dysregulated in the whole embryo.…”

Section: Discussionmentioning

confidence: 99%

Sin3a Associated Protein 130kDa, sap130, plays an evolutionary conserved role in zebrafish heart development

DeMoya

Forman-Rubinsky

Fontaine

et al. 2023

Preprint

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Hypoplastic left heart syndrome (HLHS) is a congenital heart disease where the left ventricle is reduced in size. A forward genetic screen in mice identified SIN3A associated protein 130kDa (Sap130), a protein in the chromatin modifying SIN3A/HDAC1 complex, as a gene contributing to the digenic etiology of HLHS. Here, we report the role of zebrafish sap130 genes in heart development. Loss of sap130a, one of two Sap130 orthologs, resulted in smaller ventricle size, a phenotype reminiscent to the hypoplastic left ventricle in mice. While cardiac progenitors were normal during somitogenesis, diminution of the ventricle size suggest the Second Heart Field (SHF) was the source of the defect. To explore the role of sap130a in gene regulation, transcriptome profiling was performed after the heart tube formation to identify candidate pathways and genes responsible for the small ventricle phenotype. Genes involved in cardiac differentiation and cell communication were dysregulated in sap130a, but not in sap130b mutants. Confocal light sheet analysis measured deficits in cardiac output in MZsap130a supporting the notion that cardiomyocyte maturation was disrupted. Lineage tracing experiments revealed a significant reduction of SHF cells in the ventricle that resulted in increased outflow tract size. These data suggest that sap130a is involved in cardiogenesis via regulating the accretion of SHF cells to the growing ventricle and in their subsequent maturation for cardiac function. Further, genetic studies revealed an interaction between hdac1 and sap130a, in the incidence of small ventricles. These studies highlight the conserved role of Sap130a and Hdac1 in zebrafish cardiogenesis.

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Section: Discussionmentioning

confidence: 99%

Sin3a Associated Protein 130kDa, sap130, plays an evolutionary conserved role in zebrafish heart development

DeMoya

Forman-Rubinsky

Fontaine

et al. 2023

Preprint

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“…Increasing evidence has point out that neural signals are required for the development and regeneration of tissues by interacting with stem/progenitor cells in tissues including skin, kidney, and bone marrow. 61 – 63 Activation of adrenergic signaling leads to “unhealing wounds” resembling the tumor microenvironment. 64 Thus, cancer cells could construct the innervation patterns through secreted factors (e.g.…”

Section: Discussionmentioning

confidence: 99%

Cancer cell employs a microenvironmental neural signal trans-activating nucleus-mitochondria coordination to acquire stemness

Gao

et al. 2023

Sig Transduct Target Ther

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Cancer cell receives extracellular signal inputs to obtain a stem-like status, yet how tumor microenvironmental (TME) neural signals steer cancer stemness to establish the hierarchical tumor architectures remains elusive. Here, a pan-cancer transcriptomic screening for 10852 samples of 33 TCGA cancer types reveals that cAMP-responsive element (CRE) transcription factors are convergent activators for cancer stemness. Deconvolution of transcriptomic profiles, specification of neural markers and illustration of norepinephrine dynamics uncover a bond between TME neural signals and cancer-cell CRE activity. Specifically, neural signal norepinephrine potentiates the stemness of proximal cancer cells by activating cAMP-CRE axis, where ATF1 serves as a conserved hub. Upon activation by norepinephrine, ATF1 potentiates cancer stemness by coordinated trans-activation of both nuclear pluripotency factors MYC/NANOG and mitochondrial biogenesis regulators NRF1/TFAM, thereby orchestrating nuclear reprograming and mitochondrial rejuvenating. Accordingly, single-cell transcriptomes confirm the coordinated activation of nuclear pluripotency with mitochondrial biogenesis in cancer stem-like cells. These findings elucidate that cancer cell acquires stemness via a norepinephrine-ATF1 driven nucleus-mitochondria collaborated program, suggesting a spatialized stemness acquisition by hijacking microenvironmental neural signals.

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“…Like AGTR1, the alpha-adrenergic receptor ADRA1A mediates its action through association with G-proteins that activate a phosphatidylinositol calcium second messenger system. These in turn activate mitogenic responses and regulate the growth and proliferation mediated by Klf15 in the kidney [ 48 ]. Additionally, the loss of foot processes may be explained by SHROOM2 , which is involved in endothelial cell morphology changes during cell spreading [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Unveiling Angiotensin II and Losartan-Induced Gene Regulatory Networks Using Human Urine-Derived Podocytes

Thimm

Erichsen

Wruck

et al. 2023

IJMS

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Podocytes are highly specialized cells that play a pivotal role in the blood filtration process in the glomeruli of the kidney, and their dysfunction leads to renal diseases. For this reason, the study and application of this cell type is of great importance in the field of regenerative medicine. Hypertension is mainly regulated by the renin–angiotensin–aldosterone system (RAAS), with its main mediator being angiotensin II (ANG II). Elevated ANG II levels lead to a pro-fibrotic, inflammatory, and hypertrophic milieu that induces apoptosis in podocytes. The activation of RAAS is critical for the pathogenesis of podocyte injury; as such, to prevent podocyte damage, patients with hypertension are administered drugs that modulate RAAS signaling. A prime example is the orally active, non-peptide, selective angiotensin-II-type I receptor (AGTR1) blocker losartan. Here, we demonstrate that SIX2-positive urine-derived renal progenitor cells (UdRPCs) and their immortalized counterpart (UM51-hTERT) can be directly differentiated into mature podocytes. These podocytes show activation of RAAS after stimulation with ANG II, resulting in ANG II-dependent upregulation of the expression of the angiotensin-II-type I receptor, AGTR1, and the downregulated expression of the angiotensin-II-type II receptor 2 (AGTR2). The stimulation of podocytes with losartan counteracts ANG II-dependent changes, resulting in a dependent favoring of the specific receptor from AGTR1 to AGTR2. Transcriptome analysis revealed 94 losartan-induced genes associated with diverse biological processes and pathways such as vascular smooth muscle contraction, the oxytocin signaling pathway, renin secretion, and ECM-receptor interaction. Co-stimulation with losartan and ANG II induced the exclusive expression of 106 genes associated with DNA methylation or demethylation, cell differentiation, the developmental process, response to muscle stretch, and calcium ion transmembrane transport. These findings highlight the usefulness of UdRPC-derived podocytes in studying the RAAS pathway and nephrotoxicity in various kidney diseases.

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Adrenergic receptor signaling induced by Klf15, a regulator of regeneration enhancer, promotes kidney reconstruction

Cited by 10 publications

References 44 publications

Sin3a Associated Protein 130kDa, sap130, plays an evolutionary conserved role in zebrafish heart development

Sin3a Associated Protein 130kDa, sap130, plays an evolutionary conserved role in zebrafish heart development

Cancer cell employs a microenvironmental neural signal trans-activating nucleus-mitochondria coordination to acquire stemness

Unveiling Angiotensin II and Losartan-Induced Gene Regulatory Networks Using Human Urine-Derived Podocytes

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