Calcineurin-inhibition Results in Upregulation of Local Renin and Subsequent Vascular Endothelial Growth Factor Production in Renal Collecting Ducts.
BACKGROUND
Tacrolimus (Tac) and Cyclosporine A (CyA) calcineurin inhibitors (CNIs) are 2 effective immunosuppressants which are essential to prevent allograft rejection. Calcineurin inhibitors are known to be nephrotoxic. However, the precise mechanism of nephrotoxicity is not fully understood. In this study, we investigated the in vivo effects of CNIs on the local renal renin-angiotensin system in the collecting duct (CD).


METHODS
Three-week-old mice were treated with either vehicle, CyA (2 mg/kg per day), Tac (0.075 mg/kg per day), CyA + Aliskiren (25 mg/kg per day), or Tac + Aliskiren for 3 weeks. Serum creatinine was measured. Renin and vascular endothelial growth factor (VEGF) contents in CD were evaluated with flow cytometry and multiphoton microscopy. The diameter of vessels was assessed with multiphoton microscopy, and the amount of renal collagen was determined by real-time polymerase chain reaction and Masson staining.


RESULTS
The elevated level of serum creatinine in CNI groups was abolished by Aliskiren. Flow cytometric analysis found elevated renin content in principal cells, which was prevented by Aliskiren. This result was further confirmed with multiphoton microscopy. The VEGF content in CD correlated with reduced capillary diameter and with the formation of fibrotic islands.


CONCLUSIONS
Calcineurin inhibitors induce production of renin in the CD that may contribute to decreased renal blood flow. In turn, CD responds with increased VEGF production, resulting in disproportional vessel growth, further worsening the local hypoxia and striped fibrosis surrounding the CDs. Aliskiren, a direct renin inhibitor blocks these effects and improves CNI-induced nephropathy by decreasing renin production in the CDs. Our data suggest that Aliskiren may be used for the prevention of CNI nephrotoxicity.
First Department of Pediatrics, Semmelweis University, Budapest, Hungary.
Ágnes
Á
Prókai
First Department of Pediatrics, Semmelweis University, Budapest, Hungary.
Rózsa
R
Csohány
First Department of Pediatrics, Semmelweis University, Budapest, Hungary.|MTA-SE, Pediatrics and Nephrology Research Group, Budapest, Hungary.
Erna
E
Sziksz
First Department of Pediatrics, Semmelweis University, Budapest, Hungary.
Domonkos
D
Pap
First Department of Pediatrics, Semmelweis University, Budapest, Hungary.
Leonóra
L
Balicza-Himer
First Department of Pediatrics, Semmelweis University, Budapest, Hungary.
Szilvia
S
Boros
Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
Balázs
B
Magda
First Department of Pediatrics, Semmelweis University, Budapest, Hungary.|MTA-SE, Pediatrics and Nephrology Research Group, Budapest, Hungary.
Ádám
Á
Vannay
Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary.|MTA-SE Molecular Biophysics Research Group, Budapest, Hungary.
Katalin
K
Kis-Petik
First Department of Pediatrics, Semmelweis University, Budapest, Hungary.
Andrea
A
Fekete
Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA.|Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA.
János
J
Peti-Peterdi
First Department of Pediatrics, Semmelweis University, Budapest, Hungary.|MTA-SE, Pediatrics and Nephrology Research Group, Budapest, Hungary.
Attila J
AJ
Szabó
D000577:Amides / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers / Q000097:blood; D065095:Calcineurin Inhibitors; D002196:Capillaries / Q000378:metabolism / Q000473:pathology; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine; D019610:Cytoprotection; D004195:Disease Models, Animal; D005355:Fibrosis; D005434:Flow Cytometry; D005650:Fumarates / Q000494:pharmacology; D007166:Immunosuppressive Agents; D007674:Kidney Diseases / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D007685:Kidney Tubules, Collecting / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D036641:Microscopy, Fluorescence, Multiphoton; D060888:Real-Time Polymerase Chain Reaction; D012079:Renal Circulation; D012083:Renin / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects*; D016559:Tacrolimus; D013997:Time Factors; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D000092502:Renin Inhibitors
D000577:Amides; D015415:Biomarkers; D065095:Calcineurin Inhibitors; D024042:Collagen Type I; D003404:Creatinine; D016572:Cyclosporine; D005650:Fumarates; D007166:Immunosuppressive Agents; D012083:Renin; D016559:Tacrolimus; D042461:Vascular Endothelial Growth Factor A; D000092502:Renin Inhibitors; C467480:vascular endothelial growth factor A, mouse; C446481:aliskiren