Regulation of glomerular heparanase expression by aldosterone, angiotensin II and reactive oxygen species.
BACKGROUND
Inhibition of the renin-angiotensin-aldosterone system (RAAS) provides renoprotection in adriamycin nephropathy (AN), along with a decrease in overexpression of glomerular heparanase. Angiotensin II (AngII) and reactive oxygen species (ROS) are known to regulate heparanase expression in vivo. However, it is unknown whether this is also the case for aldosterone. Therefore, we further assessed the role of aldosterone, AngII and ROS in the regulation of glomerular heparanase expression.


METHODS
Six weeks after the induction of AN, rats were treated with vehicle (n = 8), lisinopril (75 mg/L, n = 10), spironolactone (3.3 mg/day, n = 12) or the combination of lisinopril and spironolactone (n = 14) for 12 weeks. Age-matched healthy rats served as controls (n = 6). After 18 weeks, renal heparanase and heparan sulfate (HS) expression were examined by immunofluorescence staining. In addition, the effect of aldosterone, AngII and ROS on heparanase expression in cultured podocytes was determined.


RESULTS
Treatment with lisinopril, spironolactone or their combination significantly blunted the increased glomerular heparanase expression and restored the decreased HS expression in the GBM. Addition of aldosterone to cultured podocytes resulted in a significantly increased heparanase mRNA and protein expression, which could be inhibited by spironolactone. Heparanase mRNA and protein expression in podocytes were also significantly increased after stimulation with AngII or ROS.


CONCLUSIONS
Our in vivo and in vitro results show that not only AngII and ROS, but also aldosterone is involved in the regulation of glomerular heparanase expression.
van den Hoven
Mabel J
MJ
Nijmegen Centre for Molecular Life Sciences, Department of Nephrology, Radboud University Nijmegen Medical Centre, The Netherlands.
Waanders
Femke
F
Rops
Angelique L
AL
Kramer
Andrea B
AB
van Goor
Harry
H
Berden
Jo H
JH
Navis
Gerjan
G
van der Vlag
Johan
J
D000450:Aldosterone / Q000378:metabolism / Q000494:pharmacology*; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D004317:Doxorubicin / Q000633:toxicity; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D007674:Kidney Diseases / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D008297:Male; D050199:Podocytes / Q000187:drug effects / Q000201:enzymology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D013148:Spironolactone / Q000494:pharmacology; D000099175:Heparanase
D000450:Aldosterone; D000804:Angiotensin II; D000806:Angiotensin-Converting Enzyme Inhibitors; D017931:DNA Primers; D004317:Doxorubicin; D005966:Glucuronidase; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D013148:Spironolactone; D000099175:Heparanase