A novel mouse model of advanced diabetic kidney disease

Currently available rodent models exhibit characteristics of early diabetic nephropathy (DN) such as hyperfiltration, mesangial expansion, and albuminuria yet features of late DN (hypertension, GFR decline, tubulointerstitial fibrosis) are absent or require a significant time investment for full phe...

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Bibliographic Details
Published in:PloS one 2014-12, Vol.9 (12), p.e113459-e113459
Main Authors: Thibodeau, Jean-Francois, Holterman, Chet E, Burger, Dylan, Read, Naomi C, Reudelhuber, Timothy L, Kennedy, Christopher R J
Format: Article
Language:English
Subjects:
Albuminuria - pathology
Analysis
Angiotensin
Angiotensins
Animal models
Animals
Biology and Life Sciences
Consortia
Diabetes
Diabetes mellitus
Diabetes Mellitus, Experimental - complications
Diabetes Mellitus, Experimental - physiopathology
Diabetic nephropathies
Diabetic Nephropathies - physiopathology
Diabetic nephropathy
Disease Models, Animal
Fibrosis
Genetic engineering
Genomics
Hospitals
Humans
Hyperfiltration
Hyperglycemia
Hypertension
Hypertension - physiopathology
Hypertrophy
Inulin
Kidney - pathology
Kidney diseases
Kidney Glomerulus - pathology
Kidney transplantation
Medicine
Medicine and Health Sciences
Mice
Mice, Transgenic
Nephrology
Nephropathy
Pathogenesis
Physiology
Renin
Renin - genetics
Rodents
Scars
Streptozocin
Transgenic animals
Transgenic mice
Transthyretin
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Description
Summary:Currently available rodent models exhibit characteristics of early diabetic nephropathy (DN) such as hyperfiltration, mesangial expansion, and albuminuria yet features of late DN (hypertension, GFR decline, tubulointerstitial fibrosis) are absent or require a significant time investment for full phenotype development. Accordingly, the aim of the present study was to develop a mouse model of advanced DN with hypertension superimposed (HD mice). Mice transgenic for human renin cDNA under the control of the transthyretin promoter (TTRhRen) were employed as a model of angiotensin-dependent hypertension. Diabetes was induced in TTRhRen mice through low dose streptozotocin (HD-STZ mice) or by intercrossing with OVE26 diabetic mice (HD-OVE mice). Both HD-STZ and HD-OVE mice displayed more pronounced increases in urinary albumin levels as compared with their diabetic littermates. Additionally, HD mice displayed renal hypertrophy, advanced glomerular scarring and evidence of tubulointerstitial fibrosis. Both HD-OVE and HD-STZ mice showed evidence of GFR decline as FITC-inulin clearance was decreased compared to hyperfiltering STZ and OVE mice. Taken together our results suggest that HD mice represent a robust model of type I DN that recapitulates key features of human disease which may be significant in studying the pathogenesis of DN and in the assessment of putative therapeutics.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0113459