Dynamic blood pressure load and nephropathy in the ZSF1 (fa/facp) model of type 2 diabetes

Griffin, Karen A.; Abu-Naser, Mohammad; Abu-Amarah, Isam; Picken, Maria M.; Williamson, G.A.; Bidani, A.

doi:10.1152/ajprenal.00511.2006

Cited by 47 publications

(53 citation statements)

References 70 publications

(162 reference statements)

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“…Consistent with the above hypothesis, the present data indicate that renal autoregulation was markedly impaired in ZDF rats at spontaneous levels of mean BP, reducing preglomerular vascular tone and participating in glomerular hyperfiltration. However, our results seem different from those of Griffin et al [35], who found that renal autoregulation was preserved in Zucker spontaneously hypertensive rats, an offspring from the breeding of Zucker obese and spontaneously hypertensive rats. Genetic differences between ZL and ZDF rats, such as differences in leptin receptors, might cause the autoregulatory curve to shift toward higher pressure in ZDF rats.…”

Section: Discussioncontrasting

confidence: 99%

Altered gap junctional communication and renal haemodynamics in Zucker fatty rat model of type 2 diabetes

et al. 2011

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Aims/hypothesis We examined the link between altered gap junctional communication and renal haemodynamic abnormalities in diabetes in studies performed on Zucker lean (ZL) and the Zucker diabetic fatty (ZDF) rat model of type 2 diabetes. Methods The abundance of connexin (Cx) 37, 40 and 43 was assessed by western blot and immunohistochemistry. Renal haemodynamics was characterised with GAP peptides, which are Cx mimetics, to inhibit gap junctions as a probe in both strains. Results ZDF rats exhibited higher plasma glucose, 8-epiprostaglandin F2α excretion, renal plasma flow and GFR than ZL rats. In ZDF rat kidney phosphorylation of Cx43 was enhanced compared with that in ZL rats. Immunohistochemical study revealed that the density of abundance of Cx37 in renin-secreting cells was significantly reduced in ZDF rats. Although renal autoregulation was markedly impaired in ZDF rats, it was preserved in ZL rats. GAP27 for Cx37,43 and for Cx40 impaired renal autoregulation in ZL rats, but failed to induce further alterations in renal autoregulation in ZDF rats. Conclusions/interpretation Our findings indicate that ZDF rats have glomerular hyperfiltration with impaired autoregulation. They also demonstrate enhanced phosphorylation of Cxs and reduced production of Cxs in ZDF rat kidney, especially of Cx37 in renin-secreting cells. Finally, our data suggest that an impairment of gap junctional communication in juxtaglomerular apparatus plays a role in altered renal autoregulation in diabetes.

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Section: Discussioncontrasting

confidence: 99%

Altered gap junctional communication and renal haemodynamics in Zucker fatty rat model of type 2 diabetes

et al. 2011

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“…Data were acquired at 1,000 Hz in 10 s bursts every 2 min. Systolic BP is reported in order to maintain consistency with previous studies in the literature [7,14,16] and because it is more closely correlated with organ damage than mean or diastolic BP [10]. Body weight and blood glucose were measured twice weekly in all animals; blood samples were acquired from the tail of conscious, unrestrained rats.…”

Section: Methodsmentioning

confidence: 99%

“…Hypertension is generally accepted to be a major contributor to the development of nephropathy in diabetes [2,3] and accelerates all other forms of nephropathy [4]. There is also considerable evidence for the importance of genetic and functional factors in determining target organ susceptibility [5][6][7]. In uncomplicated type 1 or type 2 diabetes, there is a high incidence of diabetic hyperfiltration, which results from glomerular hypertension, presumably because of inappropriately low pre-glomerular resistance [2,8].…”

Section: Introductionmentioning

confidence: 99%

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Increased susceptibility to hypertensive renal disease in streptozotocin-treated diabetic rats is not modulated by salt intake

et al. 2012

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Aims/hypothesis In early type 1 diabetes mellitus, renal salt handling is dysregulated, so that the glomerular filtration rate becomes inversely proportional to salt intake. The salt paradox occurs in both humans and rats and, with low salt intake, results in diabetic hyperfiltration. We tested whether increased salt intake could reduce the susceptibility to injury of non-clipped kidneys in diabetic rats with pre-existing Goldblatt hypertension. Methods Male Long-Evans rats were made hypertensive and half were then made diabetic. Blood glucose was maintained at ∼20-25 mmol/l by insulin implants. One half of each received only the salt in normal chow (1% by weight) and the other half received added salt in drinking water to equal 2.7% by weight of food intake. Weekly 24 h blood pressure records were acquired by telemetry during the 4-month experiment. Results Systolic blood pressure was not affected by diabetes or increased salt intake, alone or together. Autoregulation was highly efficient in the non-clipped kidney of both intact and diabetic rats. Histological examination showed minor injury in the clipped kidney, which did not differ among groups. The non-clipped kidney showed extensive pressuredependent glomerular and vascular injury in both intact and diabetic rats. Conclusions/interpretation The relationship between pressure and injury was shifted toward lower blood pressure in diabetic rats, indicating that diabetes increased the susceptibility of the kidney to injury despite preservation of autoregulation. The increased susceptibility was not affected by high salt intake in the diabetic rats, thus disproving the hypothesis.

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“…Both lean and obese animals inherit the gene for hypertension from the SHR strain and have similarly elevated blood pressure, but only obese ZSF1 rats (fa/fa cp ) develop dyslipidemia, hyperglycemia, and renal sclerosis and fibrosis (Tofovic et al 2000, Zhang et al 2007, Rafikova et al 2008. Recently, Griffin et al (2007) demonstrated that the development of kidney disease in the ZSF1 rat model is largely independent of hypertension and/or its potential renal transmission. Thus, the ZSF1 rat model allows for separation of renal pathophysiology strictly due to obesity, hyperglycemia, and dyslipidemia from changes due to hypertension.…”

Section: Introductionmentioning

confidence: 99%

Diabetic nephropathy and long-term treatment effects of rosiglitazone and enalapril in obese ZSF1 rats

Bilan¹,

Salah²,

Bastacky³

et al. 2011

Journal of Endocrinology

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Diabetic nephropathy (DN) is a major cause of end-stage renal disease. Yet the pathogenic mechanisms underlying the development of DN are not fully defined, partially due to lack of suitable models that mimic the complex pathogenesis of renal disease in diabetic patients. In this study, we describe early and late renal manifestations of DN and renal responses to long-term treatments with rosiglitazone or high-dose enalapril in ZSF1 rats, a model of metabolic syndrome, diabetes, and chronic renal disease. At 8 weeks of age, obese ZSF1 rats developed metabolic syndrome and diabetes (hyperglycemia, glucosuria, hyperlipidemia, and hypertension) and early signs of renal disease (proteinuria, glomerular collagen IV deposition, tubulointerstitial inflammation, and renal hypertrophy). By 32 weeks of age, animals developed renal histopathology consistent with DN, including mesangial expansion, glomerulosclerosis, tubulointerstitial inflammation and fibrosis, tubular dilation and atrophy, and arteriolar thickening. Rosiglitazone markedly increased body weight but reduced food intake, improved glucose control, and attenuated hyperlipidemia and liver and kidney injury. In contrast, rosiglitazone markedly increased cardiac hypertrophy via a blood pressure-independent mechanism. High-dose enalapril did not improve glucose homeostasis, but normalized blood pressure, and nearly prevented diabetic renal injury. The ZSF1 model thus detects the clinical observations seen with rosiglitazone and enalapril in terms of primary and secondary endpoints of cardiac and renal effects. This and previous reports indicate that the obese ZSF1 rat meets currently accepted criteria for progressive experimental diabetic renal disease in rodents, suggesting that this may be the best available rat model for simulation of human DN.

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Dynamic blood pressure load and nephropathy in the ZSF1 (fa/fa^cp) model of type 2 diabetes

Cited by 47 publications

References 70 publications

Altered gap junctional communication and renal haemodynamics in Zucker fatty rat model of type 2 diabetes

Altered gap junctional communication and renal haemodynamics in Zucker fatty rat model of type 2 diabetes

Increased susceptibility to hypertensive renal disease in streptozotocin-treated diabetic rats is not modulated by salt intake

Diabetic nephropathy and long-term treatment effects of rosiglitazone and enalapril in obese ZSF1 rats

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