Rosiglitazone treatment restores renal responsiveness to atrial natriuretic peptide in rats with congestive heart failure.

Ilia Goltsman,Joseph Winaver,Doron Aronson,Omri Nativ,Emad E. Khoury,Giora Z. Feuerstein,Zaid Abassi

doi:10.1111/jcmm.14366

Abstract

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 TZDs at the renal collecting duct. A recent study from our group revealed that prolonged rosiglitazone (RGZ) treatment caused no Na+/H2O 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 ACE2, 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 ACE2, CFTR and V2 receptor. The possibility that TZD treatment in uncomplicated CHF may be less detrimental than thought before deserves additional investigations.

Highlights

Congestive heart failure and type 2 diabetes mellitus (T2DM) are leading causes of morbidity and mortality in developed countries.[1,2] due to the substantial burden of these two clinical con‐ ditions confounded by their combination, pharmacotherapy for DM faces the challenges of successfully managing the disease consider‐ ing the accompanying restrictions imposed by congestive heart failure (CHF) and of modulating the cardiovascular risk inherent to T2DM.[3]
We have demonstrated that chronic RGZ treatment caused no further increase in plasma volume com‐ pared with vehicle‐treated CHF rats, no increase in renal expres‐ sion of Na+ transport‐linked channels/transporters, no association with any deterioration in selected biomarkers of CHF and did not TA B L E 1 Probes used for validation of PPARgamma‐regulated gene targets
The current study provides additional insights into the effects of RGZ on the renal response to various natriuretic and vasodilatory compounds including atrial natriuretic peptide (ANP), Ach and SNAP in rats with compensated CHF and assesses the impact of RGZ on gene expression related to the ANP signalling pathway

Summary

Introduction

Congestive heart failure and type 2 diabetes mellitus (T2DM) are leading causes of morbidity and mortality in developed countries.[1,2] due to the substantial burden of these two clinical con‐ ditions confounded by their combination, pharmacotherapy for DM faces the challenges of successfully managing the disease consider‐ ing the accompanying restrictions imposed by CHF and of modulating the cardiovascular risk inherent to T2DM.[3]. The aim of the present study was to explore potential mechanism(s) that may underlie RGZ adverse effects in CHF

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Methods

Conclusion