Renin and prorenin activate pathways implicated in organ damage in human mesangial cells independent of angiotensin II production.
BACKGROUND
The mechanism by which an activated renin-angiotensin system (RAS) leads to the development of renal diseases, such as fibrosis, is only partially explained by the downstream effects of angiotensin II. The discovery of a receptor that binds renin and prorenin, and the consequent production of profibrotic molecules, revealed a novel axis within the RAS pathway that may contribute to the pathogenesis of organ damage in patients with elevated renin and/or prorenin levels.


METHODS
To better understand the genes and networks underlying the receptor-mediated effects of renin and prorenin, a gene expression profiling study was performed on human mesangial cells in the presence of angiotensin-II-blocking agents.


RESULTS
Renin and prorenin induce highly overlapping gene expression signatures that are dependent, only in part, on the presence of the (pro)renin receptor. We found that 2 distinct pathways were activated by renin and prorenin: a TGFbeta-dependent pathway and a TGFbeta-independent pathway. Bioinformatic analysis was used to show that both pathways are highly enriched with genes implicated in fibrosis, hypertrophy and atherosclerosis.


CONCLUSIONS
This study suggests that both renin and inactive prorenin are capable of inducing genetic programs that could contribute to end-organ damage and atherogenesis, through receptor-mediated angiotensin-independent mechanisms.
Melnyk
Roman A
RA
Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Kirkland, Que., Canada. roman_melnyk@merck.com
Tam
John
J
Boie
Yves
Y
Kennedy
Brian P
BP
Percival
M David
MD
D000804:Angiotensin II / Q000096:biosynthesis; D002478:Cells, Cultured; D002648:Child; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000209:etiology*; D008297:Male; D050527:Mesangial Cells; D008875:Middle Aged; D012083:Renin / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D000804:Angiotensin II; D012083:Renin