Genetic background influences cardiac phenotype in murine chronic kidney disease

Neuburg, Samantha; Dussold, Corey; Gerber, Claire; Wang, Xueyan; Francis, CM; Qi, Lixin; David, Véronique; Wolf, Myles; Martin, Aline

doi:10.1093/ndt/gfx332

Cited by 28 publications

(36 citation statements)

References 42 publications

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“…It has been hypothesized that long-term exposure at very high FGF23 concentrations, as the case in patients with late stages of CKD, who can develop up to 1,000-fold elevations for months ( 174 , 175 ), causes pathological cardiac remodeling and contributes to uremic cardiomyopathy ( 109 , 176 – 178 ). Such a hypothesis is supported by a recent study in mice lacking the alpha 3 chain of type IV collagen (Col4a3), a genetic animal model for CKD ( 179 ). Dependent on the genetic background, these mice either develop fast-progressing kidney injury and die at around 10 weeks of age, or the development of severe kidney injury takes longer resulting in extended survival until about 20 weeks ( 180 , 181 ).…”

Section: Effects Of Fgf23 On the Heartmentioning

confidence: 88%

“…Dependent on the genetic background, these mice either develop fast-progressing kidney injury and die at around 10 weeks of age, or the development of severe kidney injury takes longer resulting in extended survival until about 20 weeks ( 180 , 181 ). Although both mouse lines show the same degree in blood pressure elevations, only slow-progressing Col4a3 knockout mice develop cardiac hypertrophy and fibrosis which is accompanied by increased cardiac expression levels of FGFR4 ( 179 ). At 10 weeks of age, fast-progressing Col4a3 knockout mice show significantly higher elevations in intact FGF23 concentrations than slow progressors.…”

Section: Effects Of Fgf23 On the Heartmentioning

confidence: 99%

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FGF23 Actions on Target Tissues—With and Without Klotho

2018

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Fibroblast growth factor (FGF) 23 is a phosphaturic hormone whose physiologic actions on target tissues are mediated by FGF receptors (FGFR) and klotho, which functions as a co-receptor that increases the binding affinity of FGF23 for FGFRs. By stimulating FGFR/klotho complexes in the kidney and parathyroid gland, FGF23 reduces renal phosphate uptake and secretion of parathyroid hormone, respectively, thereby acting as a key regulator of phosphate metabolism. Recently, it has been shown that FGF23 can also target cell types that lack klotho. This unconventional signaling event occurs in an FGFR-dependent manner, but involves other downstream signaling pathways than in “classic” klotho-expressing target organs. It appears that klotho-independent signaling mechanisms are only activated in the presence of high FGF23 concentrations and result in pathologic cellular changes. Therefore, it has been postulated that massive elevations in circulating levels of FGF23, as found in patients with chronic kidney disease, contribute to associated pathologies by targeting cells and tissues that lack klotho. This includes the induction of cardiac hypertrophy and fibrosis, the elevation of inflammatory cytokine expression in the liver, and the inhibition of neutrophil recruitment. Here, we describe the signaling and cellular events that are caused by FGF23 in tissues lacking klotho, and we discuss FGF23’s potential role as a hormone with widespread pathologic actions. Since the soluble form of klotho can function as a circulating co-receptor for FGF23, we also discuss the potential inhibitory effects of soluble klotho on FGF23-mediated signaling which might—at least partially—underlie the pleiotropic tissue-protective functions of klotho.

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Section: Effects Of Fgf23 On the Heartmentioning

confidence: 88%

Section: Effects Of Fgf23 On the Heartmentioning

confidence: 99%

FGF23 Actions on Target Tissues—With and Without Klotho

2018

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“…The phenotype of C57BL/6 Col4a3 knockout mice was milder than that of 129Sv mice, which correlated with prolonged survival of the C57BL/6 mice. After 20 weeks, the C57BL/6 mice developed CKD associated with functional and structural symptoms of cardiac remodeling [94]. This emphasizes the importance of the genetic background of the mice used in relation to the severity of cardiac disease.…”

Section: Genetically Induced Modelsmentioning

confidence: 99%

“…Reduction or inhibition of LVH might be achieved by non-specific treatments such as reduction of hypervolemia, lowering of blood pressure and treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers that exhibit potential direct effects on the myocardium [16,94]. Further strategies to prevent left-ventricular remodeling in patients with mild-to-moderate CKD comprise of reducing overweightness and avoiding hemoglobin concentrations that are too high [98].…”

Section: Potential Therapeutic Targets Of Cardiac Remodeling In Ckdmentioning

confidence: 99%

Cardiac Remodeling in Chronic Kidney Disease

Kaesler

Babler

Floege

et al. 2020

Toxins

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Cardiac remodeling occurs frequently in chronic kidney disease patients and affects quality of life and survival. Current treatment options are highly inadequate. As kidney function declines, numerous metabolic pathways are disturbed. Kidney and heart functions are highly connected by organ crosstalk. Among others, altered volume and pressure status, ischemia, accelerated atherosclerosis and arteriosclerosis, disturbed mineral metabolism, renal anemia, activation of the renin-angiotensin system, uremic toxins, oxidative stress and upregulation of cytokines stress the sensitive interplay between different cardiac cell types. The fatal consequences are left-ventricular hypertrophy, fibrosis and capillary rarefaction, which lead to systolic and/or diastolic left-ventricular failure. Furthermore, fibrosis triggers electric instability and sudden cardiac death. This review focuses on established and potential pathophysiological cardiorenal crosstalk mechanisms that drive uremia-induced senescence and disease progression, including potential known targets and animal models that might help us to better understand the disease and to identify novel therapeutics.

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“…Although both mouse lines show the same degree in blood pressure elevations, only slow-progressing Col4a3 knockout mice develop cardiac hypertrophy and fibrosis. 15 The cardiac alterations in slowprogressing Col4a3 knockout mice is accompanied by increased cardiac expression of FGFR4. Of note, at 10 weeks of age fast-progressing Col4a3 knockout mice show significantly higher elevations in intact FGF23 concentrations than slow progressors (about 30-vs. 2fold).…”

mentioning

confidence: 99%