Effects of genetic hypertension on diabetic nephropathy in the rat ??? functional and structural characteristics

Cooper, Mark E.; Allen, Terri J.; O’Brien, Richard C; Macmillan, Pauline A.; Clarke, Belinda; Jerums, George; Doyle, Austin E.

doi:10.1097/00004872-198812000-00009

Cited by 101 publications

(87 citation statements)

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“…However, in our model, diabetes induced in DS rats resulted in a rapid development of glomerulopathy mostly characterised by mesangial expansion typical of the advanced phase of diabetic nephropathy. The relationship between hypertension and changes in kidney function and morphology in rats with streptozotocin-induced diabetes has previously been evaluated in two studies on spontaneously hypertensive rats (SHR) [23,24]. The SHR rats are considered to be salt-insensitive.…”

Section: Discussionmentioning

confidence: 99%

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Rapid development of glomerulosclerosis in diabetic Dahl salt-sensitive rats

et al. 1997

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Summary Diabetic nephropathy tends to develop more readily in patients with a family history of hypertension and/or disturbances in sodium transport across the plasma membrane. This prompted us to study the renal effects of diabetes mellitus in a rat strain which is predisposed to develop salt-sensitive hypertension, the Dahl salt-sensitive rat. Diabetes is associated with several aberrations in the renal handling of sodium, such as elevation of tubular Na + , K + ATPase activity. This effect was more pronounced in Dahl salt-sensitive than in Dahl salt-resistant rats. Severe renal lesions, characteristic of the advanced phase of diabetic nephropathy are very rarely observed in rats with streptozotocin diabetes. However, 2 months after induction of diabetes, the Dahl salt-sensitive rats had morphological signs of advanced glomerular disease. The urinary albumin concentration was very high, but did not correlate with the blood pressure. Non-diabetic Dahl salt-sensitive rats as well as Dahl salt-resistant diabetic and non-diabetic rats had little or no signs of glomerular disease and consistently very low urinary albumin concentrations. [Diabetologia (1997) 40: 367-373]

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Section: Discussionmentioning

confidence: 99%

“…In one study [23] no difference was found between SHR and WKY rats with regard to the development of diabetic nephropathy. In the other study [24] the rats were followed for 8 months after the induction of diabetes. The blood pressure in these SHR rats was higher than in our DSD rats.…”

Section: Discussionmentioning

confidence: 99%

Rapid development of glomerulosclerosis in diabetic Dahl salt-sensitive rats

et al. 1997

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“…The research project was approved by the Animal Ethics Committee of the Austin and Repatriation Medical Centre. Diabetes was induced by tail vein injection of streptozotocin (Boehringer-Mannheim, Mannhein, Germany) at a dose of 45 mg/kg in citrate buffer after a 16-h fast [23]. Long-acting insulin (Protophane, Novo Nordisk Pharmaceuticals Pty., Denmark) at a dose of 4 U/day was given to all diabetic animals by subcutaneous injection to avoid ketonuria and promote weight gain.…”

Section: Methodsmentioning

confidence: 99%

Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy

et al. 2003

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Aims. Although ACE inhibitors slow progression of diabetic renal disease, the mortality and morbidity is still high. As other hormonal factors are involved, inhibition of vasopeptidases could further reduce progression. We studied dual inhibition of angiotensin converting enzyme and neutral endopeptidase in a model of progressive diabetic renal injury. The major endpoints were reductions in systemic blood pressure, albuminuria and renal structural injury. Methods. Diabetic spontaneously hypertensive rats were treated with the ACE inhibitor perindopril (mg·kg −1 · day −1 ) or the vasopeptidase inhibitor omapatrilat at doses of 10 (oma10) and 40 (oma40) mg·kg −1 ·day −1 for 32 weeks. In vivo ACE and NEP inhibition was quantitated by in vitro autoradiography. Renal structural injury was assessed by measurement of the glomerulosclerotic (GS) index and tubulointerstitial area (TI). The expression of transforming growth factor β, β-inducible geneh3 and nephrin were also quantitated.Results. Despite a similar reduction in blood pressure by perindopril and oma10, greater attenuation of albuminuria was afforded by oma10, with a complete amelioration observed with oma40. Oma40 lead to a 33% reduction in renal NEP binding and this was associated with less albuminuria and prevention of GS, TI area and overexpression of TGFβ and βig-h3. Diabetes-associated reduction in nephrin expression was restored by both drugs. Conclusion/Interpretation. These findings suggest that other vasoactive mechanisms in addition to angiotensin II are important in the prevention of diabetic nephropathy, and that vasopeptidase inhibition might confer an advantage over blockade of the RAS alone in the treatment of diabetic renal disease. [Diabetologia (2003) 46:961-971]

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“…These investigators have concluded that pre-existing hypertension may have an important role in the progression of diabetic renal disease. 18 Similarly, it has been demonstrated that the combination of diabetes and hypertension (diabetic SHRs) lead to early and more severe markers of DR, both functional and morphological. Dosso et al 19 have shown that basement membrane thickness and increased permeability to serum albumin were observed in normotensive diabetic rats (diabetic WKY); however, these abnormalities were significantly enhanced when diabetes was combined with hypertension (diabetic SHRs).…”

Section: Experimental Evidence That Hypertension Aggravates Diabetic mentioning

confidence: 99%

“…17 However, most of these studies were performed in a genetic model of hypertension, namely a spontaneously hypertensive rat (SHR) that was rendered diabetic by injection of streptozotocin. In these rats, studies by Cooper et al 18 were the first to demonstrate that when compared with the genetically diabetic normotensive rats, specifically Wistar Kyoto (WKY) rats, diabetic SHR showed features of accelerated nephropathy, as evidenced by a 10-fold increase in albuminuria and a more pronounced thickness of glomerular basement membrane. These investigators have concluded that pre-existing hypertension may have an important role in the progression of diabetic renal disease.…”

Section: Experimental Evidence That Hypertension Aggravates Diabetic mentioning

confidence: 99%

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

2011

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Diabetes and hypertension frequently coexist and constitute the most notorious combination for the pathogenesis of diabetic nephropathy and retinopathy. Large clinical trials have clearly demonstrated that tight control of glycemia and/or blood pressure significantly reduces the incidence and progression of diabetic retinopathy (DR) and nephropathy. However, the mechanism by which hypertension interacts with diabetes to induce and/or exacerbate nephropathy and retinopathy is very unclear. Substantial evidence implicates the involvement of chronic inflammation and oxidative stress in the pathogenesis of DR and nephropathy. In addition, hypertension causes oxidative stress and inflammation in the kidney and retina. In the present review, we summarized data obtained from our research along with those from other groups to better understand the role of hypertension in the pathogenesis of diabetic nephropathy and retinopathy. It is suggested that oxidative stress and inflammation may be common denominators of kidney and retinal damage in the concomitant presence of diabetes and hypertension.

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Effects of genetic hypertension on diabetic nephropathy in the rat ??? functional and structural characteristics

Cited by 101 publications

References 0 publications

Rapid development of glomerulosclerosis in diabetic Dahl salt-sensitive rats

Rapid development of glomerulosclerosis in diabetic Dahl salt-sensitive rats

Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

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