Cardiorenal syndrome: pathophysiology and potential role of uremic toxins

2017-05-18T03:02:54Z (GMT) by Liu, Shan
Cardiorenal syndrome (CRS) describes both heart and kidney failure initiated by dysfunction in either the heart or kidney. CRS is associated with significant worsened outcomes than disease of either organ alone. The pathophysiology of this condition is still not fully understood. Specifically, there is no preclinical study examining the heart-kidney interactions where chronic heart failure (CHF) is complicated by the addition of chronic kidney disease (CKD). Conversely, the findings remain controversial in a recently described animal model recapitulating features of CKD comorbid with CHF. Furthermore, one under-explored factor contributory to the development of CRS may be circulating toxins in patients with CKD. Indoxyl sulfate (IS), one such non-dialysable uremic toxin, has direct pro-hypertrophic and pro-fibrotic effects on cardiac myocytes and fibroblasts. Increased cardiac fibrosis in animals with CKD is correlated with IS serum levels. This thesis therefore aimed to further explore the pathophysiology of CRS and the potential role of IS in this condition. The first part of the thesis evaluated cardiac and renal changes (molecular, structural and functional) and examined potential mechanisms that may underlie the changes observed in a state of chronic abnormalities in cardiac function causing progressive CKD [myocardial infarction (MI) followed by 5/6 nephrectomy (STNx) model in Chapter 3 and 4]. This is the first preclinical model (MI+STNx) to demonstrate the left ventricular (LV) dysfunction complicated by the addition of CKD. This in vivo MI+STNx study demonstrated that subsequent STNx accelerated the reduction in left ventricular ejection fraction (LVEF) post-MI. Combined MI and STNx led to increases in heart and lung weights and elevation in myocyte cross-sectional area and cardiac interstitial fibrosis in the non-infarcted myocardium compared to MI alone. These changes were associated with significant increases in atrial natriuretic peptide (ANP), transforming growth factor β1 (TGF-β1) and collagen I gene expression. Comorbid disease also caused increases in renal tubulointerstitial fibrosis compared to STNx alone, with no further deterioration in renal function. The second part of this thesis assessed pathophysiological changes and potential mechanisms in a condition of CKD contributing to decreased cardiac function and cardiac hypertrophy [STNx followed by MI (STNx+MI) model in Chapter 5 and 6]. This in vivo study demonstrated that STNx+MI caused a non-significant decrease in changes of LVEF over time compared to MI alone. Compared to STNx alone, combined STNx and MI increased renal tubulointerstitial fibrosis and kidney injury molecule-1 (KIM-1) tissue levels in the kidney, and elevated myocyte cross-sectional area and cardiac interstitial fibrosis in the non-infarcted myocardium. These changes were associated with increases in collagen I gene expression, and activation of p38 mitogen-activated protein kinase (MAPK) and p44/42 MAPK protein in the noninfarcted myocardium. The third part of the thesis focused on potential approaches to block IS-induced cardiac remodelling (Chapter 7). Organic anion transporters 1 and 3 (OAT1/3) have been found to be involved in the trans-cellular transport of IS in renal cells. Furthermore, apoptosis signal-regulating kinase-1 (ASK1) is a potential therapeutic target for cardiac disease. The activation of ASK1 associated signalling pathways, namely p38, p44/42 MAPK and nuclear factor-kappa B (NFκB), has been demonstrated to be involved in IS-induced cardiac remodelling. Hence, we investigated the role of OAT1/3 and/or ASK1 in cardiac remodelling in vitro via the approaches to block pro-hypertrophic and pro-fibrotic actions of IS in cardiac myocytes and fibroblasts. Inhibition of OAT1/3 and ASK1 suppressed IS-activated cardiac myocyte hypertrophy and fibroblast collagen synthesis, in a dose-dependent manner. OAT1/3 and ASK1 antagonists appear to attenuate these effects by blocking the uptake of IS into cardiac cells and downstream actions post-uptake, respectively. Together, this thesis has demonstrated that accelerated cardiac remodelling and increased renal tubulointerstitial fibrosis appear to be the common pathophysiological changes in the setting of MI+STNx and STNx+MI. MI+STNx animals had decreased LVEF compared to the STNx+MI animals, suggesting animals with pre-morbid CHF had worsening cardiac outcomes. A non-significant reduction in glomerular filtration rate (GFR) was observed in STNx+MI vs MI+STNx animals, indicating that animals with pre-morbid CKD were likely to develop more severe renal outcomes. Thus, the severity of heart and kidney damage appears to be best related to the primary failing organ. OAT1/3 and ASK1 appear to play a role in IS-induced pathological cardiac remodelling, which are suppressed by their antagonists, in a dose-dependent manner. They may represent potential novel therapeutic approaches to ameliorate uremic toxinstimulated cardiac effects in the setting of co-morbid CHF and CKD.