The effect of ramipril on albumin excretion in diabetes and hypertension: the role of increased lysosomal activity and decreased transforming growth factor-beta expression.
OBJECTIVE
Albumin excretion is modulated post-filtration by lysosomal processing that produces a spectrum of albumin-derived material in urine, much of which is not detected by conventional immunoassays. This study aimed to determine the efficacy of ramipril treatment (+ RAM) after 24 weeks on total albumin excretion (intact plus albumin-derived peptides) in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats with (d) and without (c) diabetes.


METHODS
Intact albumin excretion was analysed by radioimmunoassay and total albumin excretion was analysed by measuring radioactivity derived from circulating [ C]albumin. Renal lysosomal activity was determined by urinary [ H]dextran sulphate desulphation. Renal transforming growth factor-beta 1 (TGF-beta 1), TGF-beta inducible gene-h3 (beta ig-h3) and angiotensinogen mRNA production were analysed by real time reverse transcriptase-polymerase chain reaction.


RESULTS
Hypertension (SHR-c and SHR-d) resulted in a significant increase in intact albumin excretion, which was significantly reduced by ramipril treatment (P < 0.05 for SHR-c + RAM and 0.001 for SHR-d + RAM compared to non-treated). This was accompanied by a significant decrease in blood pressure (P < 0.001 for SHR-c + RAM and SHR-d + RAM), renal beta ig-h3 mRNA production (P < 0.05 for SHR-c + RAM and SHR-d + RAM), and an increase in lysosomal activity. Diabetes (WKY-d and SHR-d) primarily caused a significant increase in total albumin excretion, predominantly in the form of albumin-derived fragments in the WKY-d group and intact albumin in the SHR-d group. Ramipril treatment reduced total albumin excretion in the WKY-d + RAM group (P < 0.001).


CONCLUSIONS
Ramipril prevents increases in both intact albumin and total albumin excretion in hypertensive and diabetic states, respectively.
Russo
Leileata M
LM
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
Brammar
Gail C
GC
Jerums
George
G
Comper
Wayne D
WD
Osicka
Tanya M
TM
D000419:Albuminuria / Q000652:urine*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D001794:Blood Pressure; D003920:Diabetes Mellitus / Q000652:urine*; D016326:Extracellular Matrix Proteins / Q000235:genetics; D006973:Hypertension / Q000503:physiopathology / Q000652:urine*; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D017257:Ramipril / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D000099222:betaIG-H3 Protein
D000806:Angiotensin-Converting Enzyme Inhibitors; D000808:Angiotensinogen; D016326:Extracellular Matrix Proteins; D012333:RNA, Messenger; D017257:Ramipril; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000099222:betaIG-H3 Protein; C508962:Tgfb1 protein, rat