Open AccessRosiglitazone treatment restores renal responsiveness to atrial natriuretic peptide in rats with congestive heart failure
Author(s) -
Goltsman Ilia,
Khoury Emad E.,
Aronson Doron,
Nativ Omri,
Feuerstein Giora Z.,
Winaver Joseph,
Abassi Zaid
Publication year - 2019
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.14366
Subject(s) - atrial natriuretic peptide , medicine , rosiglitazone , endocrinology , heart failure , cyclic guanosine monophosphate , kidney , receptor , nitric oxide
The thiazolidinedione ( TZD ) class of Peroxisome proliferator‐activated receptor gamma agonists has restricted clinical use for diabetes mellitus due to fluid retention and potential cardiovascular risks. These side effects are attributed in part to direct salt‐retaining effect of TZD s at the renal collecting duct. A recent study from our group revealed that prolonged rosiglitazone ( RGZ ) treatment caused no Na+/H 2 O retention or up‐regulation of Na + transport‐linked channels/transporters in experimental congestive heart failure ( CHF ) induced by surgical aorto‐caval fistula ( ACF ). The present study examines the effects of RGZ on renal and cardiac responses to atrial natriuretic peptide ( ANP ), Acetylcholine (Ach) and S‐Nitroso‐ N ‐acetylpenicillamine ( SNAP ‐ NO donor). Furthermore, we assessed the impact of RGZ on gene expression related to the ANP signalling pathway in animals with ACF . Rats subjected to ACF (or sham) were treated with either RGZ (30 mg/kg/day) or vehicle for 4 weeks. Cardiac chambers pressures and volumes were assessed invasively via Miller catheter. Kidney excretory and renal hemodynamic in response to ANP , Ach and SNAP were examined. Renal clearance along with cyclic guanosine monophosphate ( cGMP ), gene expression of renal CHF ‐related genes and ANP signalling in the kidney were determined. RGZ ‐treated CHF rats exhibited significant improvement in the natriuretic responses to ANP infusion. This ‘sensitization’ to ANP was not associated with increases in neither urinary cGMP nor in vitro cGMP production. However, RGZ caused down‐regulation of several genes in the renal cortex (Ace, Nos3 and Npr1) and up‐regulation of ACE 2, Agtrla, Mme and Cftr along down‐regulation of Avpr2, Npr1,2, Nos3 and Pde3 in the medulla. In conclusion, CHF + RGZ rats exhibited significant enhancement in the natriuretic responses to ANP infusion, which are known to be blunted in CHF . This ‘sensitization’ to ANP is independent of cGMP signalling, yet may involve post‐ cGMP signalling target genes such as ACE 2, CFTR and V2 receptor. The possibility that TZD treatment in uncomplicated CHF may be less detrimental than thought before deserves additional investigations.