Renoprotective and anti-hypertensive effects of combined valsartan and perindopril in progressive diabetic nephropathy in the transgenic (mRen-2)27 rat.
BACKGROUND
We have previously reported that severe glomerulosclerosis progressively develops in the streptozotocin (STZ) diabetic transgenic (mRen-2)27 rat. In this diabetic model, monotherapy with either angiotensin converting enzyme inhibition (ACEI) or angiotensin type 1 (AT(1)) receptor blockade is largely renoprotective. The objective of the present study was to determine if a combination therapy at lower doses than monotherapy would confer greater renoprotection.


METHODS
At 6 weeks of age, non-diabetic control and STZ diabetic female heterozygous Ren-2 rats were randomized to receive vehicle, the AT(1) receptor blocker valsartan (V, 20 mg/kg/day), the ACEI perindopril (P, 6 mg/kg/day), or a combination of low-dose V+P (V, 3 mg/kg/day plus P, 0.5 mg/kg/day) for 12 weeks.


RESULTS
Systolic blood pressure was lowered with all treatments, but the greatest reductions were observed with V monotherapy and combination V+P therapy. All treatments reduced albuminuria, the decline in glomerular filtration rate, and cortical collagen staining, to the same extent. The glomerulosclerotic index was increased with diabetes and reduced with V and P monotherapy. However, the low-dose combination therapy was more effective than single therapy and reduced severe glomerulosclerosis to levels observed in non-diabetic controls.


CONCLUSIONS
Monotherapy with either V or P reduced blood pressure and retarded the decline in renal function and glomerulosclerosis in the diabetic Ren-2 rat. Combination therapy has the additional benefit of requiring only low doses of AT(1) receptor blockade and ACEI to achieve superior renoprotective effects in this diabetic nephropathy model.
Wilkinson-Berka
J L
JL
Department of Physiology, The University of Melbourne, Australia.
Gibbs
N J
NJ
Cooper
M E
ME
Skinner
S L
SL
Kelly
D J
DJ
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D030801:Animals, Genetically Modified; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000503:physiopathology* / Q000517:prevention & control; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D006579:Heterozygote; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D020913:Perindopril / Q000627:therapeutic use*; D051381:Rats; D012083:Renin / Q000235:genetics*; D013777:Tetrazoles / Q000627:therapeutic use*; D014633:Valine / Q000031:analogs & derivatives / Q000627:therapeutic use*; D000068756:Valsartan
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D013777:Tetrazoles; D000068756:Valsartan; D012083:Renin; D014633:Valine; D020913:Perindopril