Cardiomyocytes bind and activate native human prorenin : role of soluble mannose 6-phosphate receptors.
Cardiomyocytes bind, internalize, and activate recombinant human prorenin through mannose 6-phosphate/insulin-like growth factor II (M6P/IGFII) receptors. To investigate whether this also applies to native human prorenin, neonatal rat myocytes were incubated for 4 hours at 37 degrees C with various prorenin-containing human body fluids. Uptake and activation by M6P/IGFII receptors were observed for plasma prorenin from subjects with renal artery stenosis and/or hypertension and for follicular fluid prorenin. The total amount of cellular renin and prorenin (expressed as percentage of the levels of renin and prorenin in the medium) after 4 hours of incubation was 4 to 10 times lower than after incubation with recombinant human prorenin. Although plasma contains alkaline phosphatases capable of inactivating the M6P label as well as soluble M6P/IGFII receptors that block prorenin binding in a competitive manner and proteins (eg, insulin, IGFII) that increase the number of cell-surface M6P/IGFII receptors, these factors were not responsible for the modest uptake of native human prorenin. Uptake did not occur during incubation of myocytes with plasma prorenin from anephric subjects or with amniotic fluid prorenin, and this was not due to the presence of excessively high levels of M6P/IGFII receptors and/or phosphatase activity in these fluids. In conclusion, myocytes are capable of binding, internalizing, and activating native human prorenin of renal and ovarian origin through M6P/IGFII receptors. Differences in prorenin glycosylation and/or phosphorylation as well as the concentration of soluble M6P/IGFII receptors and growth factors affecting cell-surface M6P/IGFII receptor density determine the amount of prorenin entering the heart and thus cardiac angiotensin II production.
Saris
J J
JJ
Cardiovascular Research Institute COEUR, Department of Pharmacology, Internal Medicine, Erasmus University Rotterdam, The Netherlands.
Derkx
F H
FH
Lamers
J M
JM
Saxena
P R
PR
Schalekamp
M A
MA
Danser
A H
AH
D000653:Amniotic Fluid; D000804:Angiotensin II / Q000096:biosynthesis; D000818:Animals; D000831:Animals, Newborn; D001769:Blood; D002478:Cells, Cultured; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D005260:Female; D015571:Follicular Fluid; D006031:Glycosylation; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010053:Ovary / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D017527:Receptor, IGF Type 2 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012078:Renal Artery Obstruction / Q000097:blood / Q000378:metabolism; D012083:Renin / Q000378:metabolism*
D004792:Enzyme Precursors; D017527:Receptor, IGF Type 2; D011994:Recombinant Proteins; D000804:Angiotensin II; D012083:Renin