Targeting multiple pathways reduces renal and cardiac fibrosis in rats with subtotal nephrectomy followed by coronary ligation.
Multiple interacting pathways contribute to progression of renal and cardiac damage in chronic kidney disease followed by chronic heart failure (renocardiac syndrome). We hypothesized that simultaneous pharmacological modulation of critical pathways implicated in renocardiac syndrome would effectively reduce fibrosis in and preserve function of heart and kidney.



Rats were subjected to subtotal nephrectomy followed 9 weeks later by coronary artery ligation. From week 11 until week 16, rats received vehicle or losartan, or a combination of the NF-kB inhibitor PDTC, the NO donor molsidomine and superoxide dismutase mimetic tempol, or a combination of all four of these plus metoprolol together. At week 16, renal and cardiac structure, function and gene expression were assessed.



Individual and combined treatments were similarly effective in limiting cardiac fibrosis and further decline in systolic function. Combined treatment with all five drugs reduced renal fibrosis and CTGF gene expression more effectively than other strategies. Combining all five drugs reduced heart rate, inotropy and mean arterial pressure (MAP).



Thus, in our model of chronic renocardiac syndrome, combined treatments similarly decreased cardiac fibrosis and stabilized systolic function as losartan alone, perhaps suggesting a dominant role for a single factor such as angiotensin II type 1 (AT1) receptor activation or inflammation in the network of aberrant systems in the heart. However, tubulointerstitial fibrosis was most effectively reduced by a five-drug regimen, pointing to additive effects of multiple pathophysiological pathways in the kidney.
Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, the Netherlands.
N R
NR
Oosterhuis
Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, the Netherlands.|Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
L G
LG
Bongartz
Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, the Netherlands.
M C
MC
Verhaar
Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, the Netherlands.|Department of Experimental Cardiology, Thorax Center Erasmus University Medical Center, Rotterdam, the Netherlands.
C
C
Cheng
Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, the Netherlands.
Y J
YJ
Xu
Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, the Netherlands.
A
A
van Koppen
Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
M J
MJ
Cramer
Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
R
R
Goldschmeding
Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
C A
CA
Gaillard
Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
P A
PA
Doevendans
Division of Nephrology, Departments of Medicine and Physiology, University of Alberta, Edmonton, AB, Canada.
B
B
Braam
Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, the Netherlands.
J A
JA
Joles
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D059347:Cardio-Renal Syndrome / Q000188:drug therapy*; D003331:Coronary Vessels; D003497:Cyclic N-Oxides / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D005355:Fibrosis; D006321:Heart / Q000187:drug effects; D007668:Kidney / Q000187:drug effects; D007677:Kidney Function Tests; D008026:Ligation; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008790:Metoprolol / Q000494:pharmacology / Q000627:therapeutic use*; D008981:Molsidomine / Q000494:pharmacology / Q000627:therapeutic use*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009392:Nephrectomy; D020030:Nitric Oxide Donors / Q000494:pharmacology / Q000627:therapeutic use; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use*; D011917:Rats, Inbred Lew; D013113:Spin Labels; D013565:Sympatholytics / Q000494:pharmacology / Q000627:therapeutic use; D013859:Thiocarbamates / Q000494:pharmacology / Q000627:therapeutic use*
D047228:Angiotensin II Type 1 Receptor Blockers; D000975:Antioxidants; D003497:Cyclic N-Oxides; D016328:NF-kappa B; D020030:Nitric Oxide Donors; D011759:Pyrrolidines; D013113:Spin Labels; D013565:Sympatholytics; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D008981:Molsidomine; D008790:Metoprolol; D019808:Losartan; C001803:tempol
chronic kidney disease; fibrosis; heart failure; inflammation; renin-angiotensin system