Cardioprotective effect of calcineurin inhibition in an animal model of renal disease.
OBJECTIVE
Chronic kidney disease is directly associated with cardiovascular complications. Heart remodelling, including fibrosis, hypertrophy, and decreased vascularization, is frequently present in renal diseases. Our objective was to investigate the impact of calcineurin inhibitors (CNI) on cardiac remodelling and function in a rat model of renal disease.


RESULTS
Male Sprague Dawley rats were divided into six groups: sham-operated rats, 5/6 nephrectomized rats (Nx) treated with vehicle, CNI (cyclosporine A 5.0 or 7.5, or tacrolimus 0.5 mg/kg/day) or hydralazine (20 mg/kg twice a day) for 14 days, starting on the day of surgery. Creatinine clearance was significantly lower and blood pressure significantly higher in Nx rats when compared with controls. Morphological and echocardiographic analyses revealed increased left ventricular hypertrophy and decreased number of capillaries in Nx rats. Treatment with CNI affected neither the renal function nor the blood pressure, but prevented the development of cardiac hypertrophy and improved vascularization. In addition, regional blood volume improved as confirmed by contrast agent-based echocardiography. Hydralazine treatment did not avoid heart remodelling in this model. Gene expression analysis verified a decrease in hypertrophic genes in the heart of CNI-treated rats, while pro-angiogenic and stem cell-related genes were upregulated. Moreover, mobilization of stem/progenitor cells was increased through manipulation of the CD26/SDF-1 system.


CONCLUSIONS
We conclude from our studies that CNI-treatment significantly prevented cardiac remodelling and improved heart function in Nx rats without affecting renal function and blood pressure. This sheds new light on possible therapeutic strategies for renal patients at high cardiovascular risk.
Department of Internal Medicine D, University of Münster, 48149 Münster, Germany.
Giovana S
GS
Di Marco
Stefan
S
Reuter
Dominik
D
Kentrup
Lu
L
Ting
Liu
L
Ting
Alexander
A
Grabner
Annett M
AM
Jacobi
Hermann
H
Pavenstädt
Hideo A
HA
Baba
Klaus
K
Tiemann
Marcus
M
Brand
D000818:Animals; D065095:Calcineurin Inhibitors; D002908:Chronic Disease; D016572:Cyclosporine / Q000627:therapeutic use*; D006331:Heart Diseases / Q000517:prevention & control*; D017379:Hypertrophy, Left Ventricular / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007674:Kidney Diseases / Q000150:complications*; D008297:Male; D009392:Nephrectomy; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000627:therapeutic use*; D020257:Ventricular Remodeling / Q000187:drug effects
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D016559:Tacrolimus