Abstract
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.
Highlights
Chronic kidney disease (CKD) is increasing in prevalence (Eckardt et al, 2013) and is a significant public health problem due to its associated economic burden (Kerr et al, 2012)
These data provide evidence that conducting the subtotal nephrectomy model with our refined protocol in male 129S2/SV mice results in renal dysfunction, renal inflammation, and fibrosis with systemic pathologies akin to what is observed in patients
This model is suitable for testing new therapies for CKD given its progressive nature, clinically relevant biochemical measurements and cardiac dysfunction
Summary
Chronic kidney disease (CKD) is increasing in prevalence (Eckardt et al, 2013) and is a significant public health problem due to its associated economic burden (Kerr et al, 2012). The underlying mechanisms of fibrosis remain incompletely understood as it is a complex process involving a diverse array of cell types and molecular pathways, with cross-talk between cell types being evident (Gewin et al, 2017) These cell types include fibroblasts, tubular epithelial cells, macrophages, endothelial cells, dendritic cells, and lymphocytes (Boor et al, 2010). The sources of myofibroblasts within the injured kidney have been the subject of intense study, perivascular Gli+ progenitor cells have been suggested to be important (Kramann et al, 2015) Another notable feature of CKD is tubular atrophy and loss of tubular epithelial cells (Venkatachalam et al, 2015; Schelling, 2016; Webster et al, 2017). Cytokines secreted by tubular cells may act as paracrine factors to promote the production of collagenous matrix by surrounding myofibroblasts (Gewin, 2018)
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