Impact of nephron number dosing on cardiorenal damage and effects of ACE inhibition.
BACKGROUND
Low nephron number is a recently identified cause of arterial hypertension. We set out to test the effect of nephron number dosing on blood pressure and cardiorenal damage including left ventricular (LV) remodeling and function. Because exact determination of nephron number in vivo is currently not possible, we combined the Munich Wistar Frömter (MWF) genetic rat model of inborn nephron deficit with the 5/6 renal ablation model (Nx).


METHODS
To obtain distinct levels of nephron number dose (NND), rats underwent either sham-operation (Wistar-Sham NND 1.0, and MWF-Sham NND 0.6, n = 15, respectively) or 5/6 renal ablation (Nx, Wistar-Nx NND 0.17, and MWF-Nx NND 0.1, n = 20, respectively). Two additional groups were treated orally for 4 weeks with 1 mg/kg/day ramipril (Wistar-Nx-ACEI and MWF-Nx-ACEI, n = 15, respectively).


RESULTS
Systolic blood pressure (SBP), LV hypertrophy, mRNA expression of atrial natriuretic factor, LV contractility, and relaxation were exponentially correlated with NND (P < 0.0001, respectively). Creatinine clearance (Cl(Cr)) decreased, albuminuria, renal interstitial fibrosis, tubulointerstitial damage, and glomerulosclerosis index increased with lowering NND in both Wistar-Nx (NND 0.17) and MWF-Nx (NND 0.1) animals. LV perivascular and interstitial fibrosis and sarcoplasmic reticular (SR) Ca(2+) cycling were not directly related to NND. Angiotensin-converting enzyme (ACE) inhibition with ramipril demonstrated strong cardio- and renoprotective effects even in the setting of very low NND of 0.1 in MWF-Nx animals.


CONCLUSIONS
These data demonstrate that reduced nephron number is a significant, independent determinant of blood pressure, cardiorenal damage, and LV dysfunction in a direct dose-dependent way.
Rothermund
Lars
L
Institut für Klinische Pharmakologie und Toxikologie, Campus Benjamin Franklin und Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany. lars.rothermund@kfh-dialyse.de
Lorenz
Marcus
M
Schnieber
Anne
A
Eberson
Jan
J
Bauhaus
Iris
I
Bernhard Haug
Marcel
M
Schulz
Angela
A
Keller
Frieder
F
Vetter
Roland
R
Kreutz
Reinhold
R
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis; D001794:Blood Pressure / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D005355:Fibrosis; D006352:Heart Ventricles / Q000378:metabolism; D006973:Hypertension / Q000209:etiology; D009206:Myocardium / Q000473:pathology; D009399:Nephrons / Q000503:physiopathology*; D017257:Ramipril / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000096:biosynthesis; D020257:Ventricular Remodeling / Q000502:physiology
D000806:Angiotensin-Converting Enzyme Inhibitors; C506948:Atp2a2 protein, rat; D009320:Atrial Natriuretic Factor; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D017257:Ramipril; D002118:Calcium