Cardiorenal syndrome:pathophysiology and potential role of uremic toxins

Abstract

Cardiorenal syndrome (CRS) describes both heart and kidney failure initiated by\ndysfunction in either the heart or kidney. CRS is associated with significant worsened\noutcomes than disease of either organ alone. The pathophysiology of this condition is\nstill not fully understood. Specifically, there is no preclinical study examining the\nheart-kidney interactions where chronic heart failure (CHF) is complicated by the\naddition of chronic kidney disease (CKD). Conversely, the findings remain\ncontroversial in a recently described animal model recapitulating features of CKD comorbid\nwith CHF. Furthermore, one under-explored factor contributory to the\ndevelopment of CRS may be circulating toxins in patients with CKD. Indoxyl sulfate\n(IS), one such non-dialysable uremic toxin, has direct pro-hypertrophic and pro-fibrotic\neffects on cardiac myocytes and fibroblasts. Increased cardiac fibrosis in animals with\nCKD is correlated with IS serum levels. This thesis therefore aimed to further explore\nthe pathophysiology of CRS and the potential role of IS in this condition.\nThe first part of the thesis evaluated cardiac and renal changes (molecular, structural\nand functional) and examined potential mechanisms that may underlie the changes\nobserved in a state of chronic abnormalities in cardiac function causing progressive\nCKD [myocardial infarction (MI) followed by 5/6 nephrectomy (STNx) model in\nChapter 3 and 4]. This is the first preclinical model (MI+STNx) to demonstrate the\nleft ventricular (LV) dysfunction complicated by the addition of CKD.\nThis in vivo MI+STNx study demonstrated that subsequent STNx accelerated the\nreduction in left ventricular ejection fraction (LVEF) post-MI. Combined MI and STNx\nled to increases in heart and lung weights and elevation in myocyte cross-sectional area\nand cardiac interstitial fibrosis in the non-infarcted myocardium compared to MI alone.\nThese changes were associated with significant increases in atrial natriuretic peptide\n(ANP), transforming growth factor β1 (TGF-β1) and collagen I gene expression. Comorbid\ndisease also caused increases in renal tubulointerstitial fibrosis compared to\nSTNx alone, with no further deterioration in renal function.\nThe second part of this thesis assessed pathophysiological changes and potential\nmechanisms in a condition of CKD contributing to decreased cardiac function and\ncardiac hypertrophy [STNx followed by MI (STNx+MI) model in Chapter 5 and 6].\nThis in vivo study demonstrated that STNx+MI caused a non-significant decrease in\nchanges of LVEF over time compared to MI alone. Compared to STNx alone,\ncombined STNx and MI increased renal tubulointerstitial fibrosis and kidney injury\nmolecule-1 (KIM-1) tissue levels in the kidney, and elevated myocyte cross-sectional\narea and cardiac interstitial fibrosis in the non-infarcted myocardium. These changes\nwere associated with increases in collagen I gene expression, and activation of p38\nmitogen-activated protein kinase (MAPK) and p44/42 MAPK protein in the noninfarcted\nmyocardium.\nThe third part of the thesis focused on potential approaches to block IS-induced cardiac\nremodelling (Chapter 7). Organic anion transporters 1 and 3 (OAT1/3) have been\nfound to be involved in the trans-cellular transport of IS in renal cells. Furthermore,\napoptosis signal-regulating kinase-1 (ASK1) is a potential therapeutic target for cardiac\ndisease. The activation of ASK1 associated signalling pathways, namely p38, p44/42\nMAPK and nuclear factor-kappa B (NFκB), has been demonstrated to be involved in\nIS-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\npro-fibrotic actions of IS in cardiac myocytes and fibroblasts. Inhibition of OAT1/3 and\nASK1 suppressed IS-activated cardiac myocyte hypertrophy and fibroblast collagen\nsynthesis, in a dose-dependent manner. OAT1/3 and ASK1 antagonists appear to\nattenuate these effects by blocking the uptake of IS into cardiac cells and downstream\nactions post-uptake, respectively.\nTogether, this thesis has demonstrated that accelerated cardiac remodelling and\nincreased renal tubulointerstitial fibrosis appear to be the common pathophysiological\nchanges in the setting of MI+STNx and STNx+MI. MI+STNx animals had decreased\nLVEF compared to the STNx+MI animals, suggesting animals with pre-morbid CHF\nhad worsening cardiac outcomes. A non-significant reduction in glomerular filtration\nrate (GFR) was observed in STNx+MI vs MI+STNx animals, indicating that animals\nwith pre-morbid CKD were likely to develop more severe renal outcomes. Thus, the\nseverity of heart and kidney damage appears to be best related to the primary failing\norgan.\nOAT1/3 and ASK1 appear to play a role in IS-induced pathological cardiac\nremodelling, which are suppressed by their antagonists, in a dose-dependent manner.\nThey may represent potential novel therapeutic approaches to ameliorate uremic toxinstimulated\ncardiac effects in the setting of co-morbid CHF and CKD.