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Abstract
To address the pathophysiological mechanisms underlying chronic kidney disease with comorbid cardiac dysfunction, we investigated renal and cardiac, functional and structural damage when myocardial infarction (MI) was applied in the setting of kidney injury (induced by 5/6 nephrectomy—STNx). STNx or Sham surgery was induced in male Sprague–Dawley rats with MI or Sham surgery performed 4 weeks later. Rats were maintained for a further 8 weeks. Rats (n = 36) were randomized into four groups: Sham+Sham, Sham+MI, STNx+Sham and STNx+MI. Increased renal tubulointerstitial fibrosis (P < 0.01) and kidney injury molecule‐1 expression (P < 0.01) was observed in STNx+MI compared to STNx+Sham animals, while there were no further reductions in renal function. Heart weight was increased in STNx+MI compared to STNx+Sham or Sham+MI animals (P < 0.05), despite no difference in blood pressure. STNx+MI rats demonstrated greater cardiomyocyte cross‐sectional area and increased cardiac interstitial fibrosis compared to either STNx+Sham (P < 0.01) or Sham+MI (P < 0.01) animals which was accompanied by an increase in diastolic dysfunction. These changes were associated with increases in ANP, cTGF and collagen I gene expression and phospho‐p38 MAPK and phospho‐p44/42 MAPK protein expression in the left ventricle. Addition of MI accelerated STNx‐induced structural damage but failed to significantly exacerbate renal dysfunction. These findings highlight the bidirectional response in this model known to occur in cardiorenal syndrome (CRS) and provide a useful model for examining potential therapies for CRS.
Highlights
The classification and definition of cardiorenal syndrome (CRS) was proposed by Ronco et al in 2008 [1] and re-evaluated by the Acute Dialysis Quality Initiative (ADQI) in 2013 [2]
Comparing STNx+myocardial infarction (MI) to STNx+Sham, we observed a reduction in systolic function (LVEF, end systolic PV relationship (ESPVR)) following myocardial injury that was accompanied by a significant increase in interstitial cardiac fibrosis and hypertrophy, and tubulointerstitial renal fibrosis
Systolic blood pressure (SBP) is driver of cardiac and renal injury resulting in fibrosis and hypertrophy
Summary
The classification and definition of CRS was proposed by Ronco et al in 2008 [1] and re-evaluated by the Acute Dialysis Quality Initiative (ADQI) in 2013 [2]. In order to understand the process and mechanisms involved in type 4 CRS, CKD leading to chronic heart failure (CHF), studies have attempted to develop suitable animal models. Models were established using a uni-nephrectomy model of CKD followed by CHF, induced by myocardial infarction-MI. These studies did not recapitulate the phenomenon of primary renal failure as renal function was preserved in these animals [5,6,7,8]. LVH and hypertension is a consistent feature observed in early CKD patients, severe hypertension was not a feature in the uni-nephrectomy-MI model.
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