Longitudinal Changes in Measured Glomerular Filtration Rate, Renal Fibrosis and Biomarkers in a Rat Model of Type 2 Diabetic Nephropathy

Abstract

Background: Obese ZSF-1 rats display many features of human type II diabetes including nephropathy (DN). The study aimed to further understand the relevance of this model to DN, for which glomerular filtration rate (GFR), renal fibrosis and several urinary/tissue biomarkers was followed over 24 weeks in ZSF-1 rats. Methods: Intact/sham or uninephrectomized male and female ZSF-1 rats were studied. GFR was measured by transdermal clearance of fluorescein isothiocyanate-sinistrin. Urine was collected every 2-4 weeks for biomarker analysis. Renal tissue was examined histologically for fibrosis and for levels of inflammatory and fibrotic genes. Results: Male obese ZSF-1 rats demonstrated metabolic syndrome and proteinuria. Female counterparts were hyperlipidemic with delayed proteinuria, but were not hyperglycemic. Kidney hyperfiltration was observed in male obese rats in weeks 2-4 after surgery, and subsequently declined to levels significantly lower than controls. Tubulointerstitial/glomerular fibrosis in male obese rats was significantly elevated by week 12 post surgery and continued to expand in the ensuing weeks, particularly in uninephrectomized rats. Female rats had less severe fibrosis. Except for epidermal growth factor which decreased, the levels of several key inflammatory, injury and fibrotic factors were elevated in both tissue (mRNA) and urine (protein) of male obese rats. Conclusion: Male obese ZSF-1 rats represent an important DN model, manifesting key pathophysiological features including metabolic syndrome, proteinuria, progressive tubular and glomerular fibrosis, and transient hyperfiltration followed by progressive decline in renal function. Uninephrectomy significantly accelerated disease progression. Females were less severe in disease manifestation. Several urinary and tissue biomarkers were identified in the male obese rats that tracked with disease progression.

High resolution molecular and histological analysis of renal disease progression in ZSF1 fa/faCP rats, a model of type 2 diabetic nephropathy

“…While a decline in over 50% in GFR in this model has been reported by others, GFR decline is relatively modest in this model despite significant renal histopathology, and manifests only in older animals (e.g. in 44 week old animals but not in 24 or 32 week old animals) [8, 10, 28]. In previous work, it was proposed that hyperglycemia-induced hyperfiltration, in combination with higher protein intake due to hyperphagia, had an offsetting effect on GFR decline [10].…”

Diet-Induced Rodent Models of Diabetic Peripheral Neuropathy, Retinopathy and Nephropathy

“…When aged 20 weeks, obese ZSF1 rats showed renal lesion resembling early DN, such as arteriolar thickening, tubular dilation and atrophy, thickening of GBM, and mesangial expansion [84]. This model demonstrates the progression of several major features of type 2 DN, namely obesity, hyperglycemia, hyperlipidemia, and renal function decline, which is accompanied by proteinuria and kidney glomerular and tubulointerstitial fibrosis, which could be accelerated by uninephrectomy [85]. A key aspect of the ZSF1 model that differentiates it from other rodent models of DN, particularly in mice, is the development of significant tubulointerstitial fibrosis, a key feature of human DN.…”

“…As discussed throughout the article, there are a variety of diets (with different components and percentages) that promote distinct degrees of dysfunction and lesion, due to distinct impact on the metabolic pathways underlying disease appearance and evolution, as it is recognized that diabetic complications are affected by various factors, including obesity, IR, hyperglycemia, and hyperlipidemia. Additionally, it is known that there are large variations in sensitivity/resistance to hypercaloric diets between different species (a paramount example is the C57BL/6 mice versus the Wistar rat when fed with HFD [80,81]) and even for different strains of the same species [79,91,103], namely, regarding sensitivity to the development of distinct complications, as reported for retinopathy and nephropathy in the ZSF1 rat under HFD [67,85]. Age is also a bias factor, as diabetic microvascular complications may have a distinct phenotype depending on the animals' age.…”

Triptolide Attenuates Renal Tubular Epithelial-mesenchymal Transition Via the MiR-188-5p-mediated PI3K/AKT Pathway in Diabetic Kidney Disease

“…Multiple pathological changes result in progressive impairment of renal function during DKD, including accumulation of extracellular matrix, glomerulosclerosis and tubulointerstitial fibrosis 5 , 6 . Many lines of evidence support a pathogenic role for renal tubular injury in DKD 7 .…”