Heart-kidney interactions: mechanistic insights from animal models

Liu, Shan

doi:10.1152/ajprenal.00624.2017

Cited by 24 publications

(18 citation statements)

References 127 publications

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“…SCD due to VT is a major cause of mortality in CKD and ESRD, and the electrophysiologic mechanisms may be unique in these patient populations. Animal models that recapitulate the pathophysiology of CKD-associated VT are lacking 56 . In this report, we demonstrate premature mortality and VT inducibility in the majority of both genetic ( Lepr db/db eNOS −/− ) and inducible (HFD plus low dose STZ) mouse models of DKD.…”

Section: Discussionmentioning

confidence: 99%

Ventricular arrhythmias in mouse models of diabetic kidney disease

Laurita

Khan

McMahon

et al. 2021

Sci Rep

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Chronic kidney disease (CKD) affects more than 20 million people in the US, and it is associated with a significantly increased risk of sudden cardiac death (SCD). Despite the significance, the mechanistic relationship between SCD and CKD is not clear and there are few effective therapies. Using optical mapping techniques, we tested the hypothesis that mouse models of progressive diabetic kidney disease (DKD) exhibit enhanced ventricular arrhythmia incidence and underlying arrhythmia substrates. Compared to wild-type mice, both Leprdb/db eNOS−/− (2KO) and high fat diet plus low dose streptozotocin (HFD + STZ) mouse models of DKD experienced sudden death and greater arrhythmia inducibility, which was more common with isoproterenol than programmed electrical stimulation. 2KO mice demonstrated slowed conduction velocity, prolonged action potential duration (APD), and myocardial fibrosis; both 2KO and HFD + STZ mice exhibited arrhythmias and calcium dysregulation with isoproterenol challenge. Finally, circulating concentrations of the uremic toxin asymmetric dimethylarginine (ADMA) were elevated in 2KO mice. Incubation of human cardiac myocytes with ADMA prolonged APD, as also observed in 2KO mice hearts ex vivo. The present study elucidates an arrhythmia-associated mechanism of sudden death associated with DKD, which may lead to more effective treatments in the vulnerable DKD patient population.

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Section: Discussionmentioning

confidence: 99%

Ventricular arrhythmias in mouse models of diabetic kidney disease

Laurita

Khan

McMahon

et al. 2021

Sci Rep

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“…When using the TAC model to study heart failure it is important to take the cardiorenal axis into account, patients with reduced cardiac function often also experience CKD ( Harada et al, 2018 ; Kumar and Seth, 2019 ; Patel et al, 2019 ; Zaleska-Kociecka et al, 2019 ), as it has been suggested that a decline in kidney function directly contributes to further deterioration of cardiac function in patients ( Hewitson et al, 2015 ; Gnanaraj and Radhakrishnan, 2016 ). Several papers have indicated that a good animal model that properly represents the clinical manifests of CRS is lacking ( Szymanski et al, 2012 ; Tan et al, 2018 ; Liu, 2019 ). Attempts have been made to developed such CRS models; for instance showing adverse cardiac remodeling in a severe CKD model thereby mimicking aspects of CRS4 in patients ( Verhulst et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Mildly Increased Renin Expression in the Absence of Kidney Injury in the Murine Transverse Aortic Constriction Model

et al. 2021

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Cardiorenal syndrome type 2 is characterized by kidney failure as a consequence of heart failure that affects >50% of heart failure patients. Murine transverse aortic constriction (TAC) is a heart failure model, where pressure overload is induced on the heart without any systemic hypertension or its consequences. Whether renal function is altered in this model is debated, and if so, at which time post-TAC renal dysfunction starts to contribute to worsening of cardiac function. We therefore studied the effects of progressive heart failure development on kidney function in the absence of chronically elevated systemic blood pressure and renal perfusion pressure. C57BL/6J mice (N = 129) were exposed to TAC using a minimally invasive technique and followed from 3 to 70 days post-TAC. Cardiac function was determined with 3D ultrasound and showed a gradual decrease in stroke volume over time. Renal renin expression and plasma renin concentration increased with progressive heart failure, suggesting hypoperfusion of the kidney. In addition, plasma urea concentration, a surrogate marker for renal dysfunction, was increased post-TAC. However, no structural abnormalities in the kidney, nor albuminuria were present at any time-point post-TAC. Progressive heart failure is associated with increased renin expression, but only mildly affected renal function without inducing structural injury. In combination, these data suggest that heart failure alone does not contribute to kidney dysfunction in mice.

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“…The STNx model has been extensively reviewed from the point of heart-kidney interactions (Bongartz et al, 2012; Hewitson et al, 2015; Liu, 2019). A common comment in reviews of the literature is that in mice this model is highly variable if not uniformly performed and you can get conflicting results depending on the strain.…”

Section: Discussionmentioning

confidence: 99%

Refining the Mouse Subtotal Nephrectomy in Male 129S2/SV Mice for Consistent Modeling of Progressive Kidney Disease With Renal Inflammation and Cardiac Dysfunction

O’Sullivan

Finnie²,

Teenan³

et al. 2019

Front. Physiol.

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Chronic kidney disease (CKD) is prevalent worldwide and is associated with significant co-morbidities including cardiovascular disease (CVD). Traditionally, the subtotal nephrectomy (remnant kidney) experimental model has been performed in rats to model progressive renal disease. The model experimentally mimics CKD by reducing nephron number, resulting in renal insufficiency. Presently, there is a lack of translation of pre-clinical findings into successful clinical results. The pre-clinical nephrology field would benefit from reproducible progressive renal disease models in mice in order to avail of more widely available transgenics and experimental tools to dissect mechanisms of disease. Here we evaluate if a simplified single step subtotal nephrectomy (STNx) model performed in the 129S2/SV mouse can recapitulate the renal and cardiac changes observed in patients with CKD in a reproducible and robust way. The single step STNx surgery was well-tolerated and resulted in clinically relevant outcomes including hypertension, increased urinary albumin:creatinine ratio, and significantly increased serum creatinine, phosphate and urea. STNx mice developed significant left ventricular hypertrophy without reduced ejection fraction or cardiac fibrosis. Analysis of intra-renal inflammation revealed persistent recruitment of Ly6Chi monocytes transitioning to pro-fibrotic inflammatory macrophages in STNx kidneys. Unlike 129S2/SV mice, C57BL/6 mice exhibited renal fibrosis without proteinuria, renal dysfunction, or cardiac pathology. Therefore, the 129S2/SV genetic background is susceptible to induction of progressive proteinuric renal disease and cardiac hypertrophy using our refined, single-step flank STNx method. This reproducible model could be used to study the systemic pathophysiological changes induced by CKD in the kidney and the heart, intra-renal inflammation and for testing new therapies for CKD.

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Heart-kidney interactions: mechanistic insights from animal models

Cited by 24 publications

References 127 publications

Ventricular arrhythmias in mouse models of diabetic kidney disease

Ventricular arrhythmias in mouse models of diabetic kidney disease

Mildly Increased Renin Expression in the Absence of Kidney Injury in the Murine Transverse Aortic Constriction Model

Refining the Mouse Subtotal Nephrectomy in Male 129S2/SV Mice for Consistent Modeling of Progressive Kidney Disease With Renal Inflammation and Cardiac Dysfunction

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