Projects per year
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.
Original language | English |
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Article number | 1365 |
Journal | Frontiers in physiology |
Volume | 10 |
DOIs | |
Publication status | Published - 15 Nov 2019 |
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Dive into the research topics of 'Refining the Mouse Subtotal Nephrectomy in Male 129S2/SV Mice for Consistent Modeling of Progressive Kidney Disease With Renal Inflammation and Cardiac Dysfunction'. Together they form a unique fingerprint.Projects
- 4 Finished
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Selective targeting of GPR176 as a paradigm for the development of novel renal anti-fibrotic drugs
Denby, L. (Principal Investigator)
1/06/19 → 30/11/24
Project: Research
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Utilising renal ultrasound insonation to augment serum detection of miR biomarkers of renal injury - fibrosis and repair
Denby, L. (Principal Investigator) & Hughes, J. (Co-investigator)
UK industry, commerce and public corporations, BBSRC
1/10/17 → 3/12/21
Project: Research
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Dissecting the Role of miR-214 in TGF - Beta Dependent and Independent Fibrotic Renal Pathology: Studentship for James O'Sullivan
Denby, L. (Principal Investigator)
1/10/15 → 30/09/19
Project: Research
Profiles
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Jeremy Hughes
- Deanery of Clinical Sciences - Personal Chair of Experimental Nephrology
- Centre for Inflammation Research
Person: Academic: Research Active