Rat pancreatectomy combined with isoprenaline or uninephrectomy as models of diabetic cardiomyopathy or nephropathy

Abstract

Cardiovascular and renal complications are the predominant causes of morbidity and mortality amongst patients with diabetes. Development of novel treatments have been hampered by the lack of available animal models recapitulating the human disease. We hypothesized that experimental diabetes in rats combined with a cardiac or renal stressor, would mimic diabetic cardiomyopathy and nephropathy, respectively. Diabetes was surgically induced in male Sprague Dawley rats by 90% pancreatectomy (Px). Isoprenaline (Iso, 1 mg/kg, sc., 10 days) was administered 5 weeks after Px with the aim of inducing cardiomyopathy, and cardiac function and remodeling was assessed by echocardiography 10 weeks after surgery. Left ventricular (LV) fibrosis was quantified by Picro Sirius Red and gene expression analysis. Nephropathy was induced by Px combined with uninephrectomy (Px-UNx). Kidney function was assessed by measurement of glomerular filtration rate (GFR) and urine albumin excretion, and kidney injury was evaluated by histopathology and gene expression analysis. Px resulted in stable hyperglycemia, hypoinsulinemia, decreased C-peptide, and increased glycated hemoglobin (HbA1c) compared with sham-operated controls. Moreover, Px increased heart and LV weights and dimensions and caused a shift from α-myosin heavy chain (MHC) to β-MHC gene expression. Isoprenaline treatment, but not Px, decreased ejection fraction and induced LV fibrosis. There was no apparent interaction between Px and Iso treatment. The superimposition of Px and UNx increased GFR, indicating hyperfiltration. Compared with sham-operated controls, Px-UNx induced albuminuria and increased urine markers of kidney injury, including neutrophil gelatinase-associated lipocalin (NGAL) and podocalyxin, concomitant with upregulated renal gene expression of NGAL and kidney injury molecule 1 (KIM-1). Whereas Px and isoprenaline separately produced clinical endpoints related to diabetic cardiomyopathy, the combination of the two did not accentuate disease development. Conversely, Px in combination with UNx resulted in several clinical hallmarks of diabetic nephropathy indicative of early disease development.

Challenges in creating diabetes mellitus animal model for physiological research

“…In the 90% pancreatectomy model, it was found that 50% of rats still experienced hyperglycemia while the rest had normoglycemia according to their random blood glucose levels. Similar results were also seen in OGTT, where 50% of the 90% pancreatectomy rat model experienced hyperglycemia at 15-120 minutes of OGTT [19].…”

“…Streptozotocin is known to have cardiotoxic and nephrotoxic properties in experimental animals. This effect depends on the blood sugar levels of the experimental animals [19]. The toxic effect of streptozotocin can cause death in experimental animals.…”

“…The effects such as insulin deficiency and hyperglycemia can be observed immediately after surgery. This allows researchers to have full control over the onset of diabetes in experimental animals [19].…”

<p>Chrysophanol Inhibits the Progression of Diabetic Nephropathy via Inactivation of TGF-β Pathway</p>

“…In order to induce diabetes, STZ (60 mg/kg body weight, Sigma-Aldrich) was intraperitoneally injected into mice according to previous references. 14,15 When the blood glucose of mice reached approximately 20 mmol/l, CHR (50 mg/kg or 100 mg/kg) was administered orally once daily. After 4 weeks of CHR treatment, urine samples were collected (within 24 h), and the mice were sacrificed to harvest kidneys and blood for further analysis.…”