Modeling long-term diabetes and related complications in rats

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• 作者：Zsó ; fia Hajna^a ; ^b ; ¹ ; Krisztina Szabadfi^b ; ^c ; ¹ ; Zsolt Balla^d ; ² ; Zsolt Biró ; ^d ; Pé ; ter Degrell^e ; ³ ; Gergő A. Molná ; r^e ; Tamá ; s Kőszegi^f ; Valé ; ria Té ; kus^a ; ^b ; Zsuzsanna Helyes^a ; ^b ; ⁱ ; Andrá ; s Dobos^g ; Sá ; ndor Farkas^a ; ^h ; ⁴ ; Gyula Szűcs^h ; Ró ; bert Gá ; briel^b ; ^c ; Erika Pinté ; r^a ; ^b ; ^{erika.pinter@aok.pte.hu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：DN ; diabetic neuropathy ; DNP ; diabetic nephropathy ; DR ; diabetic retinopathy ; GCL ; ganglion cell layer ; IBO ; indirect binocular ophthalmoscope ; ILM ; inner limiting membrane ; INL ; inner nuclear layer ; IPL ; inner plexiform layer ; OLM ; outer limiting membrane ; ONH ; optic nerve head ; ONL ; outer nuclear layer ; OPL ; outer plexiform layer ; OS ; outer segment ; PAS ; periodic acid&ndash ; Schiff ; PB ; phosphate buffer ; PE ; pigment epithelium ; PFA ; paraformaldehyde ; PL ; photoreceptor layer ; STZ ; streptozotocin
• 刊名：Journal of Pharmacological and Toxicological Methods
• 出版年：2016
• 出版时间：March-April 2016
• 年：2016
• 卷：78
• 期：Complete
• 页码：1-12
• 全文大小：2587 K

文摘

Accurate preclinical modeling of diabetic complications such as retinopathy, nephropathy and neuropathy is crucial to enable the development of novel preventative therapies. The aims of this study were to establish a model of long-term diabetes with sustained medium scale hyperglycemia and characterize the pathological changes detectable after 4 months, with particular respect to dependence on the degree of hyperglycemia.

Methods

Streptozotocin-induced diabetic CFY rats were subjected to four different insulin substitution protocols to achieve different levels of glycemic control (Diabetic 1–4 groups). Eyes were investigated by ophthalmoscopy, kidney function by urine analysis, and neuropathy by functional tests. Retinal and renal morphological evaluations were performed by histology, immuno-histochemistry and electron microscopy.

Results

Rats of the Diabetic 3 group showed massive hyperglycemia-dependent anterior segment neovascularization, enhanced total retinal score and retinal apoptotic cell number, degeneration of dopaminergic amacrine cells, increased glomerular PAS-positivity, altered excreted total protein/creatinine ratio and cold allodynia, parallel with medium scale hyperglycemia (blood glucose level between 22 and 25 mmol/L) and satisfying state of health.

Discussion

We established a treatment protocol in rats enabling complex investigation of diabetic retinopathy, nephropathy and neuropathy on a long-term period. Clearly hyperglycemic dependent parameters of these complications serve as good outcome measures for preclinical trials. Our results provide a useful basis for designing studies for testing preventative treatments as well as other translational medical research in this field.