טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentGoltsman Ilia
SubjectEffects of Thiazolidinedione Therapy on Renal and Cardiac
Function in Rats with Experimental Congestive
Heart Failure
DepartmentDepartment of Medicine
Supervisors Professor Emeritus Joseph Winaver
Professor Zaid A. Abassi
Full Thesis textFull thesis text - English Version


Abstract

Background and Hypothesis: Congestive heart failure (CHF) and type 2 diabetes mellitus (T2DM) have reached epidemic proportions. The thiazolidinedione (TZD) class of peroxisome proliferator-activated receptor-γ agonists, albeit possessing beneficial cardiometabolic effects in T2DM, has limited use clinical use due to peripheral edema and fluid retention. These common side-effects are mainly attributed to direct salt-retaining actions of TZDs on the collecting duct of the nephron. Current guidelines prohibit the use of TZDs in patients with established CHF. Consequently, the cardio-renal effects of chronic TZD treatment in patients with CHF or experimental CHF models have not been thoroughly studied.

Rats with aorto-caval fistula (ACF) model volume-overload CHF by exhibiting neurohormonal activation, cardiac hypertrophy and renal sodium retention and thus resemble advanced CHF in humans. We hypothesized that the “CHF milieu” in rats with ACF would predispose to deterioration of fluid retention, edema formation and cardiac hypertrophy upon chronic TZD-treatment.

Methods: Male Sprague-Dawley rats that underwent either ACF or sham operation (control) were treated with either the TZD compound rosiglitazone (RGZ, 30mg/kg/d) or vehicle solution (Veh) for 4 weeks, during which cumulative urinary sodium excretion (UNaV) was determined. Plasma volume was evaluated by Evans Blue dye dilution. Cardiac pressures and volumes were assessed invasively. Renal excretory responses to extracellular fluid volume (ECFV) expansion and atrial natriuretic peptide (ANP) and renal vasodilatory responses were assessed following 2 weeks of either treatment by clearance methodology and ultrasonic flowmetry, respectively. cGMP generation and excretion were measured in-vivo and in-vitro. Finally, gene expression of renal sodium-transporting proteins, CHF-related genes and ANP signaling in the kidney and myocardium was evaluated.

Results: Compared with control? rats, control? rats displayed expanded plasma volume with unaltered cumulative UNaV. Contraintuitively, despite a greater weight gain, CHF? rats exhibited no intensification of sodium and water retention or plasma volume expansion but rather significant improvement in cumulative UNaV compared with Veh-treated counterparts. Furthermore, RGZ treatment did not significantly alter gene expression of any of the sodium-transport proteins previously implicated in TZD-induced sodium retention. Despite RGZ-induced improvements in several CHF biomarkers, including circulating aldosterone, cardiac hypertrophy, mean arterial pressure and myocardial angiotensin-converting enzyme (ACE) expression, invasively-measured cardiac function was unaffected.

Importantly, CHF? rats exhibited significant enhancement in the natriuretic responses to ECFV expansion and ANP infusion, which are known to be blunted in CHF. However, glomerular filtration rate and the renal vasodilatory response to different vasodilators remained unaltered. This "sensitization" to ANP was not associated with increases in either urinary excretion of its second messenger cGMP, or in-vitro cGMP production. RGZ-regulated post-cGMP signaling targets in CHF rats included several genes (including ACE2, CFTR and V2R).

Conclusions: In rats with ACF, RGZ does not exacerbate Na and water retention or cardiac dysfunction, thus arguing against direct renal salt and water retention as the mechanism for TZD-induced edema formation. Rather, it improves renal salt handling and ANP sensitivity, possibly through enhancement of tubular (rather than vascular) post-cGMP signaling. Thus, the possibility that TZD treatment in uncomplicated CHF may be less detrimental than thought before deserves additional investigation.