Hyperglycemia and Renal Mass Ablation Synergistically Augment Albuminuria in the Diabetic Subtotally Nephrectomized Rat: Implications for Modeling Diabetic Nephropathy

Abstract

Background/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.

The role of oxidative stress in streptozotocin-induced diabetic nephropathy in rats

“…Therefore, renal tissue of diabetic animals subjected to nephrectomy demonstrated slight, segmental and focal tubulointerstitial changes. In diabetic nephropathy, cells accumulate glycogen and collagen fibers in the mesangial region and in the basal membrane showing glomerulosclerosis, tubulointerstitial fibrosis, mesangial expansion, deposits of extracellular matrix, and tubulointerstitial changes (28,29). Therefore, this study reproduced the synergism found in the physiopathology of diabetic nephropathy by means of hemodynamic and oxidative mechanisms associated with histological changes.…”

Hyperglycemia activates the renin-angiotensin system and induces epithelial-mesenchymal transition in streptozotocin-induced diabetic kidneys

“…Excessive ROS production triggers renal fibrosis and inflammation. 20 – 27 Hyperglycemia induced ROS formation and activated NF-κB, thus resulting in increased inflammatory cytokine concentrations in the kidneys of diabetic rats. 25 Hyperglycemia-induced increase in ROS formation also activated the TLR4 signaling pathway in the cardiomyopathy of rats with STZ-induced DM.…”

Nefropatia induzida por contraste iodado e o diabetes mellitus: modelo experimental em ratos

“…(67) . Estudos in vivo demonstram que a hipertrofia renal se define como o estágio inicial da ND (68,69) .…”

“…O aumento da albuminúria nos animais diabéticos nefrectomizados reforçou a importância da nefrectomia para acelerar a progressão da ND e se confirmou como modelo amplamente utilizado em inúmeros trabalhos experimentais (35,55,68) .…”