Abstract-Intracardiac renin is considered to be involved in the pathogenesis of cardiac hypertrophy, fibrosis, and myocardial infarction. Cardiac renin is predominantly derived from the circulation, because preprorenin is not expressed locally and uptake of renin has been demonstrated. One mechanism of internalization recently described involves the mannose-6-phosphate receptor and requires glycosylation of renin. Based on previous observations, we considered the existence of another pathway of uptake, not requiring glycosylation and predominantly involving prorenin. This hypothesis and its functional consequences were investigated in vitro and in vivo. We demonstrate that isolated adult cardiomyocytes internalize unglycosylated prorenin, which is followed by the generation of angiotensins. We further show that transgenic rats, expressing the ren-2 d renin gene in an inducible manner, exhibit markedly enhanced levels of unglycosylated renin within intracellular compartments in the heart as a consequence of the induction of hepatic transgene expression and the rise of circulating unglycosylated prorenin levels. Because in this model severe cardiac damage occurs as a consequence of the rise of circulating prorenin levels, internalization of prorenin into cardiac cells is likely to play a key role in this process.

An alternative transcript of the rat renin gene was recently characterized in the adrenal gland, in addition to the known messenger RNA (mRNA) coding for preprorenin. In the alternative transcript, exon 1 is replaced by exon 1A, a domain originating in intron 1. The reading frame of this mRNA, termed exon 1A-renin transcript, codes for a truncated prorenin that presumably remains intracellular, in contrast to preprorenin, which is targeted to the secretory pathway by its prefragment. We here demonstrate the tissue-specific regulation of expression of both transcripts by RT and PCR. In many tissues both transcripts are present, for example in the adrenal gland, spleen, liver, and hypothalamus. In some organs, however, only one of the renin mRNAs is found. In the kidney only the full-length mRNA coding for preprorenin is detected. In the heart exclusively the exon 1A-mRNA is expressed, but not the preprorenin transcript. After myocardial infarction, which is known to activate the intracardiac renin-angiotensin system, expression of exon 1A-renin mRNA in the left ventricle was stimulated about 4-fold, compared with that in sham-operated animals, whereas no mRNA corresponding to preprorenin was detectable. These findings may have implications for the current concepts of local extrarenal renin-angiotensin systems, as they provide the molecular basis for a possible intracellular function of renin and exclude a role for locally produced secretory renin in the heart.

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