AIMS: 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. METHODS AND 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. CONCLUSION: 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.
AIMS: 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. METHODS AND 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. CONCLUSION: 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.
Authors: Christian Faul; Ansel P Amaral; Behzad Oskouei; Ming-Chang Hu; Alexis Sloan; Tamara Isakova; Orlando M Gutiérrez; Robier Aguillon-Prada; Joy Lincoln; Joshua M Hare; Peter Mundel; Azorides Morales; Julia Scialla; Michael Fischer; Elsayed Z Soliman; Jing Chen; Alan S Go; Sylvia E Rosas; Lisa Nessel; Raymond R Townsend; Harold I Feldman; Martin St John Sutton; Akinlolu Ojo; Crystal Gadegbeku; Giovana Seno Di Marco; Stefan Reuter; Dominik Kentrup; Klaus Tiemann; Marcus Brand; Joseph A Hill; Orson W Moe; Makoto Kuro-O; John W Kusek; Martin G Keane; Myles Wolf Journal: J Clin Invest Date: 2011-10-10 Impact factor: 14.808
Authors: Saurav Singh; Alexander Grabner; Christopher Yanucil; Karla Schramm; Brian Czaya; Stefanie Krick; Mark J Czaja; Rene Bartz; Reimar Abraham; Giovana S Di Marco; Marcus Brand; Myles Wolf; Christian Faul Journal: Kidney Int Date: 2016-07-22 Impact factor: 10.612
Authors: Giovana Seno Di Marco; Stefan Reuter; Dominik Kentrup; Alexander Grabner; Ansel Philip Amaral; Manfred Fobker; Jörg Stypmann; Hermann Pavenstädt; Myles Wolf; Christian Faul; Marcus Brand Journal: Nephrol Dial Transplant Date: 2014-05-29 Impact factor: 5.992
Authors: Giovana S Di Marco; Peter Rustemeyer; Marcus Brand; Raphael Koch; Dominik Kentrup; Alexander Grabner; Burkhard Greve; Werner Wittkowski; Hermann Pavenstädt; Martin Hausberg; Stefan Reuter; Detlef Lang Journal: PLoS One Date: 2011-09-08 Impact factor: 3.240
Authors: Dominik Kentrup; Stefan Reuter; Uta Schnöckel; Alexander Grabner; Bayram Edemir; Hermann Pavenstädt; Otmar Schober; Michael Schäfers; Eberhard Schlatter; Eckhart Büssemaker Journal: PLoS One Date: 2011-10-21 Impact factor: 3.240