Cytosolic renin is targeted to mitochondria and inducesapoptosis in H9c2 rat cardiomyoblasts

Abstract

One important goal in cardiology is to prevent necrotic cell death in the heart. Necrotic cell death attracts neutrophils and monocytes into the injured myocardium. The consequences are fibrosis, remodelling and cardiac failure. The renin-angiotensin system promotes the development of cardiac failure. Recently, alternative renin transcripts have been identified lacking the signal sequence for a cotranslational transport to the endoplasmatic reticulum. These transcripts encode for a cytosolic renin with unknown functions. The expression of this alternative transcript increases after myocardial infarction. We hypothesized that cytosolic renin plays a role in survival and death of cardiomyocytes. To test this hypothesis, we overexpressed secretory or cytosolic renin in H9c2 cardiomyblasts and determined the rate of proliferation, necrosis and apoptosis. Proliferation rate, as indicated by BrdU incorporation into DNA, was reduced by secretory and cytosolic renin (cells transfected with control vector: 0.33 ± 0.06; secretory renin: 0.12 ± 0.02; P < 0.05; cytosolic renin: 0.15 ± 0.03; P < 0.05). Necrosis was increased by secretory renin but decreased by cytosolic renin (LDH release after 10 days from cells transfected with control vector: 68.5 ± 14.9; secretory renin: 100.0 ± 0; cytosolic renin: 25.5 ± 5.3% of content, each P < 0.05). Mitochondrial apoptosis, as indicated by phosphatidylserin translocation to the outer membrane, was unaffected by secretory renin but increased by cytosolic renin (controls: 23.8 ± 3.9%; secretory renin: 22.1 ± 4.7%; cytoplasmatic renin: 41.2 ± 3.8%; P < 0.05). The data demonstrate that a cytosolic renin exists in cardiomyocytes, which in contradiction to secretory renin protects from necrosis but increases apoptosis. Non-secretory cytosolic renin can be considered as a new target for cardiac failure.

Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute?

“…A second source of renal renin is the collecting duct cells that secrete active renin into the tubular fluid (52,71,82,92,113). There is evidence for alternative gene products of intracellular renin in the kidney, brain, and adrenal that may imply a renin-dependent pathway for the intracellular expression of angiotensin peptides (65,76,106,107,142). Apart from its catalytic activity, prorenin may constitute an additional circulating hormone of the RAS through binding and activation of the prorenin receptor within various tissues (52,71,94).…”

Peptidases and the Renin-Angiotensin System: The Alternative Angiotensin-(1-7) Cascade

“…The truncated form of renin lacks the secretory signal of the protein and the enzyme is not secreted, but resides within the cell. Peters and colleagues find that truncated renin specifically localized to the mitochondria and that the active form of renin, but not prorenin, was internalized by mitochondria [14,18,19]. The overexpression of the active renin isoform protected the cells under high glucose conditions and this effect was not reversed by the renin inhibitor aliskerin or an AT 1 R antagonist suggesting that the beneficial effects may not reflect activation of the Ang II-AT 1 R axis [20].…”

Angiotensin II in Septic Shock

“…Evidence has indicated a direct interaction between angiotensin II and mitochondrial components [42][43][44][45]. In a study using 125 I-labeled angiotensin II in rats, angiotensin II was detected in the mitochondria and nuclei of the heart, brain and smooth muscle cells [42,43].…”