Key result
Mice with superimposed hypertension and diabetes developed robust features of advanced diabetic nephropathy, including a 40-fold increase in albuminuria and significant GFR decline compared to diabetic controls.
The combination of hypertension and diabetes in mice (HD mice) provides a robust model of advanced diabetic nephropathy that recapitulates key features of human disease, including GFR decline and tubulointerstitial fibrosis.
May accelerate preclinical testing of advanced diabetic nephropathy therapies; leaves open clinical translation.
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.
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Thibodeau et al. (2014) studied Diabetic Kidney Disease. Superimposed hypertension (TTRhRen) and diabetes (STZ or OVE26) vs. Wild-type, uniquely hypertensive, or uniquely diabetic mice was evaluated on Development of advanced diabetic nephropathy features (albuminuria, GFR decline, tubulointerstitial fibrosis). Mice with superimposed hypertension and diabetes developed robust features of advanced diabetic nephropathy, including a 40-fold increase in albuminuria and significant GFR decline compared to diabetic controls.
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