Impaired angiotensin II regulation of renal C-type natriuretic peptide mRNA expression in experimental diabetes mellitus.
OBJECTIVE
Abnormalities in the regulation of natriuretic peptides (NP) associated with major diseases such as hypertension, heart failure, and diabetes mellitus (DM) have been reported. We investigated levels of mRNA for the vasodilator C-type natriuretic peptide (CNP) in the renal cortex of streptozotocin (STZ)-diabetic rats and the influence of an angiotensin II inhibition.


METHODS
DM was induced in Wistar rats by a single STZ injection. Rats were kept for 12 weeks. Additionally, the influence of the ACE inhibitor ramipril (Ram: 3 mg/kg/day) and the AT1 receptor antagonist losartan (Los: 20 mg/kg/day) on CNP expression in the STZ-diabetic and control groups was studied (each group n=6). Animals were characterized by their mean arterial blood pressure, plasma glucose levels, and renal function (each group n=9). After extraction of total renal cortical RNA, CNP expression was analyzed by Northern blots.


RESULTS
Renal function was impaired in STZ-diabetic rats which has been improved by Ram and Los treatment. Untreated STZ-diabetic rats showed no difference in renal CNP expression compared to untreated controls. Ram and Los treatments led to an increase in renal cortical CNP mRNA in both diabetic and non-diabetic rats. This effect was weaker in STZ-diabetic rats (Ram: control 5.4-fold, STZ 3.5-fold; Los: control 4.2-fold, STZ 1.9-fold).


CONCLUSIONS
These results clearly demonstrate a direct regulatory effect of the renin-angiotensin system (RAS) on renal mRNA levels of CNP. We suggest that RAS inhibition not only prevents the generation of angiotensin II (AngII) but also leads to a stimulation of CNP expression. We conclude that AngII suppresses CNP expression via the AT1 receptor and this mechanism is impaired in STZ-diabetic rats.
Walther
T
T
Department of Cardiology and Pneumology, University Hospital Benjamin Franklin, Free University of Berlin, Hindenburgdamm 30, D-12200, Berlin, Germany. walther@ukbf.fu-berlin.de
Schuitheiss
H P
HP
Tschöpe
C
C
D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D015152:Blotting, Northern; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D007672:Kidney Cortex / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D008297:Male; D020098:Natriuretic Peptide, C-Type / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D017257:Ramipril / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology
D012333:RNA, Messenger; D000804:Angiotensin II; D020098:Natriuretic Peptide, C-Type; D019808:Losartan; D017257:Ramipril