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...
Background/Aims: Renin is known as a secretory glycoprotein that ultimately leads to angiotensin II generation. In this way renin exerts pro-inflammatory effects and promotes cardiac injury. Additional transcripts have been identified encoding for a cytosolic renin isoform that - in contrast to secretory renin - exhibits cardioprotective effects under ischemic conditions. The promoter of these transcripts is unknown. Methods: Using qRT-PCR and dual-luciferase reporter assay we examined the expression and promotor activity of cytosolic renin as well as the regulation by glucose starvation in H9c2 cardiomyoblasts. Results: We identified a promoter in intron1 of the rat renin gene with two glucose starvation-sensitive regions. One region contains a binding motif for serum response factor (SRF). Under glucose depletion expression of SRF increased prior to cytosolic renin. SRF knock down selectively decreased cytosolic renin expression and attenuated the increase of cytosolic renin expression under glucose depletion. Conclusions: Transcripts encoding for secretory and cytosolic renin are differentially expressed. The low basal expression of cytosolic renin as well as its induction under ischemia-related conditions represents an efficient system regulated in accordance with its previously identified unfavorable effects under control situations but protective effects seen after myocardial infarction or glucose depletion.
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