An Alternative Promoter in Intron1 of the Renin Gene is Regulated by Glucose Starvation via Serum Response Factor

Lutze, Philipp; Wanka, Heike; Bäumgen, Inga; Staar, Doreen; Grunow, Bianka; Peters, Jörg

doi:10.1159/000479209

Cited by 8 publications

(20 citation statements)

References 32 publications

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“…Overexpressing SRF by LV-SRF significantly attenuated the antiproliferative and antimigratory effects of miR-125b, suggesting that SRF is a functional downstream target of miR-125b and is involved in the miR-125b-mediated modulation of VSMC function. SRF is a highly conserved and widely expressed single-copy transcription factor that plays extensive role in circulatory system such as cardiac function and hypertension [26,27]. SRF theoretically binds up to 1, 216 permutations of a 10-base pair cis element known as the CArG box [28].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

MicroRNA-125b Affects Vascular Smooth Muscle Cell Function by Targeting Serum Response Factor

Chen

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Increasing evidence links microRNAs to the pathogenesis of peripheral vascular disease. We recently found microRNA-125b (miR-125b) to be one of the most significantly down-regulated microRNAs in human arteries with arteriosclerosis obliterans (ASO) of the lower extremities. However, its function in the process of ASO remains unclear. This study aimed to investigate the expression, regulatory mechanisms, and functions of miR125b in the process of ASO. Methods: Using the tissue explants adherent method, vascular smooth muscle cells (VSMCs) were prepared for this study. A rat carotid artery balloon injury model was constructed to simulate the development of vascular neointima, and a lentiviral transduction system was used to overexpress serum response factor (SRF) or miR-125b. Quantitative real-time PCR (qRT-PCR) was used to detect the expression levels of miR-125b and SRF mRNA. Western blotting was performed to determine the expression levels of SRF and Ki67. In situ hybridization analysis was used to analyze the location and expression levels of miR-125b. CCK-8 and EdU assays were used to assess cell proliferation, and transwell and wound closure assays were performed to measure cell migration. Flow cytometry was used to evaluate cell apoptosis, and a dual-luciferase reporter assay was conducted to examine the effects of miR-125b on SRF. Immunohistochemistry and immunofluorescence analyses were performed to analyze the location and expression levels of SRF and Ki67. Results: miR125b expression was decreased in ASO arteries and platelet-derived growth factor (PDGF)-BB-stimulated VSMCs. miR-125b suppressed VSMC proliferation and migration but promoted VSMC apoptosis. SRF was determined to be a direct target of miR-125b. Exogenous miR-125b expression modulated SRF expression and inhibited vascular neointimal formation in ballooninjured rat carotid arteries. Conclusions: These findings demonstrate a specific role of the miR-125b/SRF pathway in regulating VSMC function and suggest that modulating miR-125b levels might be a novel approach for treating ASO.

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Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

MicroRNA-125b Affects Vascular Smooth Muscle Cell Function by Targeting Serum Response Factor

Chen

Wang

et al. 2018

Cell Physiol Biochem

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“…Here, quantifying the ratio of orange (JC1 aggregates, high ΔΨ m ) to green (JC1 monomers, low ΔΨ m ) FLI allowed the estimation of ΔΨ m . We did not find any differences between control lines and ren(2)(3)(4)(5)(6)(7)(8)(9) cells as well as between scramble controls and siRNA treated H9c2 cells, indicating an identical level of ΔΨ m in all cell lines, investigated (Figure 4C, D). To visualize the mitochondrial network, H9c2 cells were additionally analysed by fluorescence microscopy using MitoTracker red and nonyl-acridine orange (NAO) labelling (Figure 5).…”

mentioning

confidence: 76%

“…17 Vice versa, an age-dependent decrease of aerobic glycolysis was accompanied by an increased mitochondrial respiration and ROS production and led finally to neuronal cell death. 17 In this sense, in ren (2)(3)(4)(5)(6)(7)(8)(9) cells the switch between mitochondrial OXPHOS and aerobic glycolysis appears to be more balanced to avoid harmful generation of ROS during ischaemia/reperfusion and to maintain a high level of energetic plasticity for surviving. A dysfunctional heart usually lacks this metabolic plasticity.…”

Section: Discussionmentioning

confidence: 99%

“…Correspondingly, inhibitors of the RAS are among the most potent drugs in the treatment of hypertension and cardiac failure, markedly increasing the life span of patients. 1 In addition to the classical renin transcript, alternative transcripts have been identified in several species including humans [termed exon (2)(3)(4)(5)(6)(7)(8)(9), exon(1A-9), renin-b, renin-c]. [2][3][4] These alternative transcripts are derived from the same renin gene, but lack exon 1.…”

Section: Introductionmentioning

confidence: 99%

“…The protein, which we henceforth term cyto-renin, lacks the prefragment and the first The transcription of cyto-renin is under the control of an alternative promoter located in intron 1. 7 This promoter has very low basal activity, but is stimulated by glucose depletion in cardiac cells 7 as well as after myocardial infarction in the rat heart. 8 Cells overexpressing cyto-renin are more resistant against necrotic death under ischaemic conditions such as glucose depletion.…”

Section: Introductionmentioning

confidence: 99%

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An alternative renin isoform is cardioprotective by modulating mitochondrial metabolism

Wanka

Lutze

Staar

et al. 2018

J Cellular Molecular Medi

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The renin‐angiotensin system promotes oxidative stress, apoptosis, necrosis, fibrosis, and thus heart failure. Secretory renin plays a central role in these processes, initiating the generation of angiotensins. Nevertheless, alternative renin transcripts exist, which code for a cytosolically localized renin isoform (cyto‐renin) that is cardioprotective. We tested the hypothesis that the protective effects are associated with a beneficial switch of metabolic and mitochondrial functions. To assess H9c2 cell mitochondrial parameters, we used the Seahorse XF analyser. Cardiac H9c2 cells overexpressing cyto‐renin exhibited enhanced nonmitochondrial oxygen consumption, lactate accumulation, and LDH activity, reflecting a switch to more aerobic glycolysis known as Warburg effect. Additionally, mitochondrial spare capacity and cell respiratory control ratio were enhanced, indicating an increased potential to tolerate stress conditions. Renin knockdown induced opposite effects on mitochondrial functions without influencing metabolic parameters. Thus, the protective effects of cyto‐renin are associated with an altered bioenergetic profile and an enhanced stress tolerance, which are favourable under ischaemic conditions. Therefore, cyto‐renin is a promising new target for the prevention of ischaemia‐induced myocardial damage.

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Non-secretory renin reduces oxidative stress and increases cardiomyoblast survival during glucose and oxygen deprivation

Wanka

Lutze

Staar

et al. 2020

Sci Rep

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Although the renin-angiotensin system usually promotes oxidative stress and cell death, renin transcripts have been discovered, whose transcription product may be cardioprotective. these transcripts encode a non-secretory renin isoform that is localized in the cytosol and within mitochondria. Here we tested the hypotheses that cytosolic renin [ren(2-9)] expression promotes cell survival under hypoxia and glucose depletion by preserving the mitochondrial membrane potential (∆Ψ m ) and mitigating the accumulation of ROS. To simulate ischemic insults, we exposed H9c2 cells to glucose deprivation, anoxia or to combined oxygen-glucose deprivation (OGD) for 24 hours and determined renin expression. Furthermore, H9c2 cells transfected with the empty pIRES vector (pIRES cells) or ren(2-9) cDNA-containing vector [ren(2-9) cells] were analyzed for cell death, ∆Ψ m , Atp levels, accumulation of RoS, and cytosolic ca 2+ content. In pIRES cells, expression of ren(1A-9) was stimulated under all three ischemia-related conditions. After oGD, the cells lost their ∆Ψ m and exhibited enhanced RoS accumulation, increased cytosolic ca 2+ levels, decreased Atp levels as well as increased cell death. In contrast, ren(2-9) cells were markedly protected from these effects. Ren(2-9) appears to represent a protective response to oGD by reducing RoS generation and preserving mitochondrial functions. therefore, it is a promising new target for the prevention of ischemia-induced myocardial damage.Myocardial infarction is a major cause of death worldwide. Given the high incidence of myocardial infarction and the associated cardiac injury, developing novel strategies and countermeasures to protect the heart against acute and especially ischemia/reperfusion-induced damage is of great interest.Renin is known as secretory glycoprotein that generates angiotensin (ANG) I from angiotensinogen. ANG I is further cleaved to ANG II by the angiotensin-converting enzyme. ANG II increases blood pressure as well as salt-and water reabsorption. Furthermore, ANG II enhances oxidative stress, exerts pro-inflammatory effects and induces apoptotic and necrotic cell death, particularly in the heart and the kidney. Correspondingly, inhibitors of the renin-angiotensin system (RAS) are among the most potent drugs in the treatment of hypertension and cardiac failure, markedly increasing the life span of patients 1 .Alternative renin transcripts, termed exon1A renin, exon(2-9)renin, renin-b or renin-c, have been identified in rats and mice 2,3 as well as in transgenic mice expressing a human renin gene construct 4 . In the rat heart, exon(1A-9) renin transcription is under the control of an alternative promoter located in intron 1 5 . In cardiac cells, this promoter is stimulated by glucose depletion in a serum response factor-dependent manner 5 . Furthermore, exon(1A-9) renin mRNA abundance increased markedly after myocardial infarction in vivo 6 . Due to the absence of the signal for a co-translational transport to the endoplasmatic reticulum, encoded by exon1, all a...

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An Alternative Promoter in Intron1 of the Renin Gene is Regulated by Glucose Starvation via Serum Response Factor

Cited by 8 publications

References 32 publications

MicroRNA-125b Affects Vascular Smooth Muscle Cell Function by Targeting Serum Response Factor

MicroRNA-125b Affects Vascular Smooth Muscle Cell Function by Targeting Serum Response Factor

An alternative renin isoform is cardioprotective by modulating mitochondrial metabolism

Non-secretory renin reduces oxidative stress and increases cardiomyoblast survival during glucose and oxygen deprivation

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