Association of Prolonged Hyperglycemia With Glomerular Hypertrophy and Renal Basement Membrane Thickening in the Goto Kakizaki Model of Non–Insulin-Dependent Diabetes Mellitus

Phillips, Aled Owain; Baboolal, Keshwar; Riley, Stephen; Gröne, H. J.; Janssen, Ulf; Steadman, Robert; Jd, Williams; Floege, Jürgen

doi:10.1053/ajkd.2001.21322

Cited by 74 publications

(52 citation statements)

References 30 publications

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“…The hypertrophy of the mesangium (one of the features of diabetic nephropathy) was also observed in Goto Kakizaki rat, a model of non-insulin-dependent diabetes mellitus [41]. A range of mechanisms have been implicated in the alterations in the structure of the kidney including the diacylglycerol-protein kinase C-extracellular regulated kinase pathway [42] and TGF-beta.…”

Section: Discussionmentioning

confidence: 96%

Saturated-fat diet induces moderate diabetes and severe glomerulosclerosis in hamsters

Popov¹,

Simionescu²,

Shepherd

2003

Diabetologia

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Aims/hypothesis. Diets high in saturated fat are thought to be a risk factor for Type 2 diabetes and associated complications. We investigated effects of a medium and high saturated fat diet on the development of diabetes-associated pathologies in Golden Syrian hamsters, an animal that reacts to dietary lipids in a fashion similar to humans. Methods. Three diets containing 46.5 kcal %, 267.3 kcal %, and 488.2 kcal % as saturated fat respectively, were studied. Metabolic parameters were measured up to 20 weeks. Electron microscopy was used to examine the structure of the pancreas, aorta and kidney. Results. Increased saturated fat consumption was associated with: (i) gradual imbalance of homeostasis, and severe structural alterations of acinar, beta cells and capillaries in the pancreas, and of the kidney glomeruli; (ii) severe hypertriglyceridaemia and augmented creatinine concentrations related to disturbances of the renal function, progressing to nodular glomerulosclerosis and nephropathy; (iii) reduced early insulin secretion in response to glucose; (iv) switch of the aortic endothelium to a secretory phenotype. Conclusion/interpretation. The results show that highcaloric saturated fat intake induced diabetes in hamsters, probably linked to delayed insulin secretion. The model was also associated with the development of a range of pathologies characteristic to human diabetes, including nephropathy and defects in vasculature. Thus, high-fat fed hamsters provide a new model that is likely to be useful in understanding the cellular and molecular mechanisms involved in the pathogenesis of diabetes. [Diabetologia (2003[Diabetologia ( ) 46:1408[Diabetologia ( -1418

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Section: Discussionmentioning

confidence: 96%

Saturated-fat diet induces moderate diabetes and severe glomerulosclerosis in hamsters

Popov¹,

Simionescu²,

Shepherd

2003

Diabetologia

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“…39 All pharmacological interventions lowered podocyte damage. Podocytes possess receptors for a variety of hormones, including adrenergic beta (2) and dopamine D(1) receptors, stimulation of which increases cAMP, 40 a potent regulator of actin assembly, cell morphology and matrix production.…”

Section: Discussionmentioning

confidence: 99%

Renoprotective effect of a dopamine D3 receptor antagonist in experimental type II diabetes

Gross

Koch

Mühlbauer

et al. 2006

Laboratory Investigation

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Diabetic nephropathy is the leading cause of end-stage renal disease. Dopamine receptors are involved in the regulation of renal hemodynamics and may play a role in diabetes-induced hyperfiltration. To test this hypothesis, we investigated the renal effect of a dopamine D3 receptor antagonist (D3-RA) in hypertensive type II diabetic SHR/N-cp rats. Lean and obese SHR/N-cp rats were randomly assigned to D3-RA, angiotensinconverting enzyme inhibitor (ACE-i), or D3-RA þ ACE-i treatment or control conditions. Treated animals were given the D3-RA A-437203 (10 mg/kg/body weight (BW)/day) or the ACE-i trandolapril (0.3 mg/kg BW/day) or a combination of both. At 6 months following perfusion, fixed kidneys were analyzed by morphological and stereological methods. Indices of renal damage (glomerulosclerosis, glomerulosclerosis damage index (GSI), tubulointerstitial and vascular damage), glomerular geometry and functional variables such as urinary albumin excretion, glomerular filtration rate, blood pressure, blood chemistry and BW were determined. The GSI (score 0-4) was significantly higher (Po0.05) in untreated diabetic animals (1.6270.3) compared to nondiabetic controls (0.470.2) and the treatment groups (D3-RA: 0.3170.12; ACE-i: 0.2970.1; combination treatment: 0.1270.01). Urinary albumin excretion (mg/24 h) was higher in untreated diabetic controls (102719) compared to nondiabetic controls (31712) and the treatment groups (D3-RA: 44715; ACE-i: 41713; combination treatment: 1578). Mean glomerular volume was higher in untreated diabetic animals compared to nondiabetic controls and to the treatment groups. Desmin expression, a marker of podocyte damage, was elevated in untreated diabetic controls and diminished in all treatment groups. These data suggest that in a model of type II diabetes, the dopamine D3-RA had a beneficial effect on renal morphology and albuminuria, which was comparable in magnitude to that of ACE-i treatment.

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“…108,[110][111][112][113][114] In addition, other phenotype such as salt-sensitive hypertension, 115 hypertriglyceridemia, endothelial dysfunction, 115 microangiopathy and macroangiopathy were observed in GK. 110 Older animals develop significant renal damage including glomerular hypertrophy, thickening of the glomerular basement membrane, proliferation of mesangial cells, glomerulosclerosis, tubulointerstitial fibrosis and inflammatory cell infiltration.…”

Section: Strain Characteristicsmentioning

confidence: 99%

“…110 Older animals develop significant renal damage including glomerular hypertrophy, thickening of the glomerular basement membrane, proliferation of mesangial cells, glomerulosclerosis, tubulointerstitial fibrosis and inflammatory cell infiltration. 113,[116][117][118] Moreover, some substrains of GK develop increased proteinuria at 24 months of age, 118 which might be affected by hypertension. 119 Furthermore, GK rats show early development of neuropathy and retinopathy late in life.…”

Section: Strain Characteristicsmentioning

confidence: 99%

Mapping genetic determinants of kidney damage in rat models

Schulz

Kreutz

2012

Hypertens Res

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During the last two decades, significant progress in our understanding of the development of kidney diseases has been achieved by unravelling the mechanisms underlying rare familial forms of human kidney diseases. Due to the genetic heterogeneity in human populations and the complex multifactorial pathogenesis of the disease phenotypes, the dissection of the genetic basis of common chronic kidney diseases (CKD) remains a difficult task. In this regard, several inbred rat models provide valuable complementary tools to uncover the genetic basis of complex renal disease phenotypes that are related to common forms of CKD. In this review, data obtained in nine experimental rat models, including the Buffalo (BUF), Dahl salt-sensitive (SS), Fawn-hooded hypertensive (FHH), Goto-Kakizaki (GK), Lyon hypertensive (LH), Munich Wistar Frömter (MWF), Sabra hypertension-prone (SBH), spontaneously hypertensive rat (SHR) and stroke-prone spontaneously hypertensive rat (SHRSP) inbred strains, that contributed to the genetic dissection of renal disease phenotypes are presented. In this panel of inbred strains, a large number of quantitative trait loci (QTL) linked to albuminuria/proteinuria and other functional or structural kidney abnormalities could be identified by QTL mapping analysis and follow-up studies including consomic and congenic rat lines. The comprehensive exploitation of the genotype-renal phenotype associations that are inherited in this panel of rat strains is suitable for making a significant contribution to the development of an integrated approach to the systems genetics of common CKD. INTRODUCTIONCommon forms of chronic kidney diseases (CKD) represent complex disease phenotypes that are influenced by both environmental and genetic factors. [1][2][3][4][5] Both arterial hypertension and type-2 diabetes mellitus are major contributors to complex CKD, which has a high prevalence in the general human population worldwide affecting B11-15% of individuals in Europe and United States. 6-9 CKD represents as expected a major risk factor for the progression to end-stage renal disease but associates also with an increased risk of cardiovascular morbidity and mortality. 10,11 In addition to the assessment of impaired renal function or glomerular filtration rate, urinary albumin excretion rate (albuminuria) represents another important clinical marker for the evaluation of CKD and cardiovascular risk of patients. [10][11][12][13][14][15] These renal disease phenotypes are also inherited in several inbred rat strains many of which are hypertensive. 16 During the last decades, genetic mapping studies by genome-wide linkage analysis followed by fine mapping of selected quantitative trait loci (QTL) for renal disease phenotypes were reported. Subsequently, studies in consomic and congenic rats were performed to further unravel the genetics of kidney injury in inbred rat strains. For QTL confirmation, consomic strains were generated by transfer of an entire chromosome carrying a QTL from a donor strain into the disease backgro...

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Association of Prolonged Hyperglycemia With Glomerular Hypertrophy and Renal Basement Membrane Thickening in the Goto Kakizaki Model of Non–Insulin-Dependent Diabetes Mellitus

Cited by 74 publications

References 30 publications

Saturated-fat diet induces moderate diabetes and severe glomerulosclerosis in hamsters

Saturated-fat diet induces moderate diabetes and severe glomerulosclerosis in hamsters

Renoprotective effect of a dopamine D3 receptor antagonist in experimental type II diabetes

Mapping genetic determinants of kidney damage in rat models

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