Comparison of renal morphology in the Streptozotocin and the SHR/N-cp models of diabetes

Abstract

The Streptozotocin (STZ) model of diabetes is commonly used for studies of diabetic nephropathy although the histological lesions of the kidney are mild and do not resemble those seen in diabetic patients. The SHR/N-cp rat model of type II diabetes spontaneously develops pronounced abnormalities in renal histology. In the present study, we compared renal morphology in the STZ rat and the diabetic SHR/N-cp rat. Sprague-Dawley rats received STZ, developed diabetes after 2 days and were treated with insulin. In the SHR/N-cp rat, obesity is inherited as an autosomal recessive trait. The progeny are either lean (used as controls) or obese and diabetic. After 6 months of observation, STZ and SHR/N-cp rats were killed. The renal damage was evaluated by assessing damage indices and by using stereological techniques. In addition, immunohistochemistry and electron microscopy were performed. The glomerular and tubulointerstitial changes were much more pronounced in the diabetic SHR/N-cp compared to the STZ model. In parallel glomerular PCNA þ cells were significantly more frequent and expression of TGF-b and PDGF by immunohistochemistry in glomeruli and in the tubulointerstitial space was more pronounced in SHR/N-cp compared to STZ rats. The glomeruli of SHR/Ncp contained less and larger podocytes as well as smaller mesangial cells embedded in more mesangial matrix compared to STZ. Similarly, less, but larger endothelial cells were found in SHR/N-cp than in STZ rats. The mean glomerular volume was similarly increased in the two models. Albumin excretion was only modestly increased in STZ diabetes, but pronounced in the SHR/N-cp rat. Although the STZ model of diabetes exhibits numerous biochemical sequelae of hyperglycemia, the morphological lesions are unimpressive. In contrast, the diabetic SHR/N-cp exhibits marked structural lesions, particularly podocyte damage and mesangial expansion that promise to make it a more suitable model for investigation of diabetic glomerulosclerosis.

Microangiopathy and visual deficits characterize the retinopathy of a spontaneously hypertensive rat model with type 2 diabetes and metabolic syndrome

“…These results suggest that target organ damage of the retina is more subtle compared with changes in peripheral organs, such as the kidney, as previously reported. 17,18 Although we performed no renal histology analysis, our data indicating marked albuminuria in obese SHR/N-cp animals are in agreement with previous findings, in which significant structural changes in the kidney have been clearly demonstrated in parallel to the albuminuria in the same model. 17 On this basis, we asked how the microvessels were affected in obese SHR/N-cp rats.…”

“…In this regard, the aim of this study was to investigate retina pathology in the SHR/N-cp model that combines type 2 diabetes and features of the metabolic syndrome, including obesity, hypertension and hyperlipidemia as well as insulin resistance. 13,15,31 In contrast to the more pronounced target organ damage previously reported in the cardiovascular system 12 and kidney, 17,18 histological analysis in this study revealed an intact integrity of the retina in obese animals. Specifically, azan and sirius red staining demonstrated no marked difference in the expression of matrix molecules.…”

“…30 Moreover, even within one condition, the manifestation and progression of the organ damage may depend on existing comorbidities, such as hypertension 4 and dyslipidemia. 9 Thus, Gross et al 17 previously demonstrated striking differences in the renal pathology between the STZ model of diabetes and the SHR/N-cp model of type 2 diabetes. They reported that diabetic animals in response to STZ treatment exhibited only modest glomerulosclerosis, tubulointerstitial damage and albuminuria, whereas the SHR/N-cp animals showed more striking glomerular and tubulointerstitial lesions combined with more pronounced albuminuria.…”

“…We therefore set out to address this point in an experimental setting by investigating the retina in the obese and spontaneously hypertensive corpulent (SHR/N-cp) rat model. 12 This model combines obesity, type 2 diabetes, hypertension and hyperlipidemia 13 and exhibits a wide range of target organ damage; atherosclerosis, 12 hepatic steatosis, 14 pancreatic islet cell hyperplasia, 15 cardiomyopathy 16 and nephropathy 17,18 have been described in SHR/ N-cp. Furthermore, this model demonstrates an important feature of the metabolic syndrome, that is, insulin resistance, 19 which has also gained importance with regard to the pathogenesis of retinopathy, particularly retinal neovascularization.…”

Improvement of insulin response in the streptozotocin model of insulin-dependent diabetes mellitus. Insulin response with and without a long-acting insulin treatment

“…Furthermore, STZ is a nephrotoxic substance and has been shown to cause renal tubular injury in patients (Weiss, 1982). The STZ treatment per se may cause urinary protein leakage (Palm et al, 2004), although -E-mail: Lina.Nordquist@medcellbiol.uu.se it does not seem to affect neither renal clearances of inulin nor para-amino-hippuric acid (Churchill et al, 1993) or cause as marked histological lesions as does diabetes in patients (Gross et al, 2004).…”