A new model of diabetic nephropathy with progressive renal impairment in the transgenic (mRen-2)27 rat (TGR)

Kelly, Darren J.; Wilkinson-Berka, Jennifer L.; Allen, Terri J.; Cooper, Mark E.; Skinner, Sandford L.

doi:10.1046/j.1523-1755.1998.00019.x

Cited by 160 publications

(168 citation statements)

References 32 publications

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“…The intrarenal RAAS is thought to be activated during diabetes, based on in vitro and in vivo evidence. 21,22,24,25,48,54,55,69,78 Therefore, the effect of renin inhibition in diabetic conditions is of great interest.…”

Section: Testing Aliskiren In Animal Modelsmentioning

confidence: 99%

“…It seems doubtful that all of the labeled aliskiren observed in glomeruli in these studies was bound to renin: it is highly unlikely that so much renin was present in the glomeruli of the normotensive rats used in this study. 69,95,96 Moreover, it seems similarly implausible that exposure to aliskiren for 2 h in normotensive rats could have induced recruitment of such high levels of glomerular renin, as has been shown in pre-glomerular vessels after chronic RAAS blockade, 97 especially as aliskiren is a relatively weak inhibitor of rat renin (Table 1). However, some of the label seen in glomeruli may have reflected aliskiren bound to renin that possibly was present in the mesangial matrix.…”

Section: Aliskiren Localizes In the Kidneymentioning

confidence: 99%

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New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

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The renin-angiotensin-aldosterone system (RAAS) has a central function in the regulation of blood pressure. Aliskiren, the first direct renin inhibitor to be approved for the treatment of hypertension, blocks the RAAS at its point of activation. As renin inhibition acts at the top of the RAAS cascade, this mechanism has been proposed to offer advantages over existing modes of RAAS blockade. The RAAS is also considered to be a major factor in the pathogenesis of many renal diseases, especially diabetic nephropathy (DN), the main cause of end-stage renal disease. Existing therapies to block the RAAS slow the progression of DN, but they do not halt the disease. Therefore, more effective modes of interventions are needed. Studies to determine the efficacy of aliskiren in human renal disease are in progress. This review summarizes in vivo studies in which the efficacy of aliskiren was tested in experimental models of renal disease, and presents in vitro studies that provide insights into the possible mechanisms by which aliskiren confers renoprotection in animals. These works are discussed in the framework of the intrarenal RAAS and suggest that aliskiren may act by unique renoprotective mechanisms. Keywords: aliskiren; kidney; mechanism; nephropathy; renin INTRODUCTIONThe renin-angiotensin-aldosterone system (RAAS) is an ancient pathway 1 that has evolved into a central mechanism by which mammalian blood pressure (BP) and fluid homeostasis are regulated. Research in this field started with the discovery in 1898 by Tigerstedt and Berman 2 that a renal extract when injected into rabbits induced a rapid increase in systemic BP. Subsequent work over many years established the RAAS as a pivotal contributor to cardiorenal diseases. Hence, inhibitors of the middle and distal portions of the RAAS pathway, angiotensin-converting enzyme (ACE) inhibitors (ACEI) and AT 1 receptor blockers, respectively, have become mainstay therapies for treating hypertension. In 2007, aliskiren, the first direct renin inhibitor (DRI), was approved for the treatment of hypertension. This heralded the therapeutic control of BP by inhibiting the RAAS at its first and rate-limiting step. However, RAAS blockade is also effective for treating renal disease 3-6 and the efficacy of aliskiren for this purpose is currently being investigated. Accordingly, the subject of this review is to summarize the preclinical evidence for renoprotection by aliskiren, and to discuss recently published information on the possible mechanism(s) for these benefits. As it is well recognized that there is a tissue as well as circulating RAAS, 7 the preclinical actions of aliskiren will be discussed in the context of the intrarenal RAAS and the potential for its inhibition by aliskiren.

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Section: Testing Aliskiren In Animal Modelsmentioning

confidence: 99%

Section: Aliskiren Localizes In the Kidneymentioning

confidence: 99%

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

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“…Histochemical analysis of renal glycogen was determined by periodic acid-Schiff (PAS) staining [10]. For determination of glycogenin protein levels, 0.4 μg phenylmethylsulfonyl fluoride (PMSF)-treated α-amylase (Sigma-Aldrich) was added to 50 μg tissue homogenate and incubated at room temperature for 20 min, prior to SDS-PAGE and subsequent western blot analysis.…”

Section: Methodsmentioning

confidence: 99%

Attenuation of Armanni–Ebstein lesions in a rat model of diabetes by a new anti-fibrotic, anti-inflammatory agent, FT011

et al. 2012

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Aims/hypothesis A key morphological feature of diabetic nephropathy is the accumulation and deposition of glycogen in renal tubular cells, known as Armanni-Ebstein lesions. While this observation has been consistently reported for many years, the molecular basis of these lesions remains unclear. Methods Using biochemical and histochemical methods, we measured glycogen concentration, glycogen synthase and glycogen phosphorylase enzyme activities, and mRNA expression and protein levels of glycogenin in kidney lysates from control and transgenic (mRen-2)27 rat models of diabetes that had been treated with and without a new antifibrotic agent, FT011.

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“…7 One group of investigators reported that STZ-induced diabetes in female heterozygous (mREN-2)27 rats recapitulates the proteinuria, nodular glomerulosclerosis, and progressive loss of renal function that are cardinal features of DN in human beings. 6 However, other investigators suggest that the survival and kidney pathology of male heterozygotes is determined more by hypertension than by diabetes, as the presence of diabetes in these animals seemed to exert little phenotypic effect. 7 A sexual dimorphism in hypertension is apparent from the lower blood pressure of female vs male (mREN-2)27 rats.…”

mentioning

confidence: 97%

“…1,2 Streptozotocin (STZ), which induces hyperglycemia by selectively damaging pancreatic b cells, has been administered to genetically modified rodents to create a variety of DN models. [3][4][5][6] The validity of one of these models, the diabetic (mREN-2)27 rat, has been questioned because of the apparent overwhelming impact of its genetically mediated hypertension on renal pathology. 7 One group of investigators reported that STZ-induced diabetes in female heterozygous (mREN-2)27 rats recapitulates the proteinuria, nodular glomerulosclerosis, and progressive loss of renal function that are cardinal features of DN in human beings.…”

mentioning

confidence: 99%

Differential contribution of diabetes and the Ren2 gene to glomerular pathology in diabetic (mREN-2)27 rats

Appelhoff

Hill

Findon

et al. 2010

Laboratory Investigation

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The effect of diabetes mellitus vs the effect of the Ren2 gene on the glomerular pathology of (mREN-2)27 heterozygous male rats is controversial. As discrete diabetes-induced glomerular lesions may have been overlooked, we performed a detailed morphometric analysis of glomeruli in diabetic and non-diabetic heterozygous male (mREN-2)27 rats and their normotensive (non-diabetic and diabetic Sprague-Dawley) controls. Glomeruli were scored by light microscopy for nine discrete histological parameters, some of which were graded for extent and/or severity. Mesangiolysis, segmental hypocellularity, and severe tuft-to-capsule adhesions were specific to diabetes; severe mesangial matrix expansion, glomerulosclerosis, thickening of Bowman's capsule, and dilatation of the urinary space were specific to the Ren2 gene. Hyalinosis and hypercellularity were associated with both diabetes and the Ren2 gene: the effect was additive for hyalinosis and synergistic for hypercellularity. The histological parameters were then combined with two physiological indices (systolic blood pressure and proteinuria) and principle components analysis (PCA) was used to detect correlations between the variables. Four discrete patterns of pathology were identified; three were statistically associated with diabetes and/or the Ren2 gene. These findings suggest that both diabetes and the Ren2 gene make significant, albeit different, contributions to the glomerular pathology of diabetic heterozygous male (mREN-2)27 rats. Despite defining the contribution of diabetes, our work does not support the (mREN-2)27 rat as a model of diabetic nephropathy (DN). Rather, it suggests that these animals remain useful for investigating a particular and limited constellation of DN features. There are numerous rodent models of human diabetic nephropathy (DN), attesting to the uncertainty associated with many of them. 1,2 Streptozotocin (STZ), which induces hyperglycemia by selectively damaging pancreatic b cells, has been administered to genetically modified rodents to create a variety of DN models. [3][4][5][6] The validity of one of these models, the diabetic (mREN-2)27 rat, has been questioned because of the apparent overwhelming impact of its genetically mediated hypertension on renal pathology. 7 One group of investigators reported that STZ-induced diabetes in female heterozygous (mREN-2)27 rats recapitulates the proteinuria, nodular glomerulosclerosis, and progressive loss of renal function that are cardinal features of DN in human beings. 6 However, other investigators suggest that the survival and kidney pathology of male heterozygotes is determined more by hypertension than by diabetes, as the presence of diabetes in these animals seemed to exert little phenotypic effect. 7 A sexual dimorphism in hypertension is apparent from the lower blood pressure of female vs male (mREN-2)27 rats. 8 This dimorphism has been proposed to underlie the apparent gender-dependent variation in experimental outcome because the effects of diabetes might only be observed in kidneys ...

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A new model of diabetic nephropathy with progressive renal impairment in the transgenic (mRen-2)27 rat (TGR)

Abstract: This is the first report of a diabetic rodent model developing rapid onset renal impairment. Furthermore, this study suggests a role for an activated renal RAS in the acceleration of diabetic renal disease and confirms the benefit of drugs that inhibit this system.

Cited by 160 publications

References 32 publications

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Attenuation of Armanni–Ebstein lesions in a rat model of diabetes by a new anti-fibrotic, anti-inflammatory agent, FT011

Differential contribution of diabetes and the Ren2 gene to glomerular pathology in diabetic (mREN-2)27 rats

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