Murine Nephrotoxic Nephritis as a Model of Chronic Kidney Disease.

M K E Ougaard,H Søndergaard,P H Kvist,I Rune,H E Jensen,C Hess

doi:10.1155/2018/8424502

M K E Ougaard, H Søndergaard + Show 4 more

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https://doi.org/10.1155/2018/8424502

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Abstract

Using the nonaccelerated murine nephrotoxic nephritis (NTN) as a model of chronic kidney disease (CKD) could provide an easily inducible model that enables a rapid test of treatments. Originally, the NTN model was developed as an acute model of glomerulonephritis, but in this study we evaluate the model as a CKD model and compare CD1 and C57BL/6 female and male mice. CD1 mice have previously showed an increased susceptibility to CKD in other CKD models. NTN was induced by injecting nephrotoxic serum (NTS) and evaluated by CKD parameters including albuminuria, glomerular filtration rate (GFR), mesangial expansion, and renal fibrosis. Both strains showed significant albuminuria on days 2-3 which remained significant until the last time point on days 36-37 supporting dysfunctional filtration also observed by a significantly declined GFR on days 5-6, 15–17, and 34–37. Both strains showed early progressive mesangial expansion and significant renal fibrosis within three weeks suggesting CKD development. CD1 and C57BL/6 females showed a similar disease progression, but female mice seemed more susceptible to NTS compared to male mice. The presence of albuminuria, GFR decline, mesangial expansion, and fibrosis showed that the NTN model is a relevant CKD model both in C57BL/6 and in CD1 mice.

Highlights

Animal models with clinical and pathological features of human chronic kidney disease (CKD) are highly warranted to advance novel therapies for CKD and would enable a deeper understanding of the pathogenesis and thereby more targetspecific therapies
C57BL/6 mice subjected to 250 μl nephrotoxic serum (NTS) showed an increased urinary albumin excretion rate (UAER) on days 9/10 compared to the groups subjected
The nonaccelerated nephrotoxic nephritis (NTN) model is a widely used model of acute GN, but no characterisation of the chronic progression of the disease is thoroughly described in mice

Summary

Introduction

Animal models with clinical and pathological features of human chronic kidney disease (CKD) are highly warranted to advance novel therapies for CKD and would enable a deeper understanding of the pathogenesis and thereby more targetspecific therapies. CKD is defined clinically by prolonged and progressive loss of kidney function measured by a declined glomerular filtration rate (GFR) and the presence of albuminuria with pathological findings of mesangial expansion, inflammation, and renal fibrosis [1]. Prior work has documented limitations of the classical murine models of CKD including the unilateral ureteral obstruction (UUO), 5/6 nephrectomy, and diabetic nephropathy models [2, 3]. The unobstructed kidney in the UUO model compensates for the loss of function in the obstructed kidney [2]. Models of diabetic nephropathy have their limitations as both the classical streptozotocin- (STZ-) induced model and the db/db model develop slowly and often only show mild signs of CKD [7]

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