Intracellular sorting of renin: cell type specific differences and their consequences.

Renin is commonly known as a secretory glycoprotein, which is expressed, stored and released in a regulated manner by the kidney. Besides this, a number of extrarenal tissues, such as adrenal gland and heart express or internalise renin. In the heart a local RAS may exert prohypertrophic, proliferative, antiproliferative or apoptotic properties. The local RAS in kidney, adrenal gland and heart are each unique and their modes of action are distinct. This is due to the expression of different renin transcripts and different intracellular sorting and transport events for renin. In the rat kidney exclusively the commonly known preprorenin is expressed encoding for secretory renin. This is targeted to lysosomes, which become secretory renin granules. The cells of the rat adrenal cortex express preprorenin as well, but this is partially targeted to the regulated secretory pathway. Rat adrenocortical cells additionally express an alternative renin transcript, termed exon1A renin, which encodes for a truncated prorenin that is imported into mitochondria. Its function is not known to date. Interestingly, in the rat heart exclusively the alternative transcript is expressed. Even in hypertrophic hearts or after myocardial infarction, preprorenin remains undetectable. Exon1A renin transcript levels, in contrast, markedly increased after myocardial ischemia. This provides a new molecular basis for a function of locally expressed renin. In addition, there are different pathways of renin internalisation by cardiac cells. A mannose-6-phosphate receptor mediated uptake has been described. We recently described another pathway independently of the mannose-6-phosphate receptor. Such a pathway is apparently of functional significance. Subsequent generation of angiotensins and myocyte hypertrophy and proliferation by prorenin through angiotensin generation has been described.