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. 2012 Jan;2(1):115-24.
doi: 10.1159/000338272. Epub 2012 May 12.

Hyperglycemia and renal mass ablation synergistically augment albuminuria in the diabetic subtotally nephrectomized rat: implications for modeling diabetic nephropathy

Li-Hao Chen  1 , Bailey Stead, Suzanne L Advani, Noreen Yaqoob, Kerri Thai, M Golam Kabir, Darren A Yuen, Kim A Connelly, Richard E Gilbert, Andrew Advani
Affiliations

Hyperglycemia and renal mass ablation synergistically augment albuminuria in the diabetic subtotally nephrectomized rat: implications for modeling diabetic nephropathy

Li-Hao Chen et al. Nephron Extra. 2012 Jan.

Abstract

BACKGROUND/AIMSBACKGROUND/AIMS: While experimental models that emulate diabetic nephropathy are valuable tools for elucidating pathogenetic mechanisms and developing novel therapies, existing models imperfectly recapitulate human disease. In diabetes, hyperglycemia and hemodynamic forces act in concert to induce renal injury. Accordingly, in the present study, we combined streptozotocin-induced diabetes with surgical ablation of 5/6 of the kidney mass with the aim of evaluating their additive effects on renal function and glomerular morphology.

Methods: Female F344 rats were randomized to undergo subtotal nephrectomy (SNx) either at baseline or following 4 weeks of diabetes.

Results: In comparison to sham rats, rats with diabetes or rats after SNx surgery, diabetic subtotally nephrectomized (DM-SNx) rats demonstrated an increase in systolic blood pressure, glomerular volume and mesangial matrix. Albuminuria was synergistically increased by hyperglycemia and renal mass ablation associated with decreased nephrin expression. In contrast, glomerular capillary rarefaction and glomerular filtration rate were similarly reduced in SNx and DM-SNx rats.

Conclusion: The DM-SNx rat recapitulates some of the features of human disease, most notably augmented albuminuria. Since this model avoids the deletion or overexpression of gene(s) linked to the pathogenesis of nephropathy, the DM-SNx rat model represents a complementary tool for the trial of novel therapies.

Keywords: Albuminuria; Diabetic nephropathy; Experimental model; Glomerular hypertrophy; Glomerulosclerosis; Nephrin; Streptozotocin; Subtotal nephrectomy.

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Figures

Fig. 1
Fig. 1
Albumin excretion rate in sham-operated, DM, SNx and DM-SNx rats. * p < 0.001 vs. all other groups. p < 0.001 for interaction.
Fig. 2
Fig. 2
Representative periodic acid-Schiff-stained kidney sections from sham-operated (a), DM (b), SNx (c) and DM-SNx (d) rats. Original magnification ×400.
Fig. 3
Fig. 3
Glomerular volume in sham-operated, DM, SNx and DM-SNx rats. * p < 0.001 vs. sham, † p < 0.01 vs. DM, ‡ p < 0.001 vs. DM, § p < 0.05 vs. SNx.
Fig. 4
Fig. 4
Representative photomicrographs of JG-12-labeled glomerular capillaries from kidney sections from sham-operated (a), DM (b), SNx (c) and DM-SNx (d) rats. Original magnification ×400. e Quantitation of JG-12 immunolabeling. * p < 0.01 vs. sham, † p < 0.001 vs. DM, ‡ p < 0.001 vs. sham.
Fig. 5
Fig. 5
Podocyte changes in DM-SNx rats. Representative photomicrographs of nephrin-immunostained kidney sections from sham-operated (a), DM (b), SNx (c) and DM-SNx (d) rats. Original magnification ×400. e Quantitation of nephrin immunostaining. Representative photomicrographs of WT1-immunostained kidney sections from sham-operated (f), DM (g), SNx (h) and DM-SNx (i) rats. Original magnification ×400. j Quantitation of WT1 immunostaining. * p < 0.001 vs. sham, † p < 0.05 vs. DM, ‡ p < 0.01 vs. SNx, § p < 0.05 vs. sham, p < 0.01 vs. sham.
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