Hypertension superimposed on type II diabetes in Goto Kakizaki rats induces progressive nephropathy

Janssen, Ulf; Riley, Stephen; Vassiliadou, Athina; Floege, Jürgen; Phillips, Aled Owain

doi:10.1046/j.1523-1755.2003.00007.x

Cited by 77 publications

(72 citation statements)

References 41 publications

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“…The clipped kidneys showed minor injury, which did not differ among groups and did not correlate with BP or blood glucose. Thus the rats showed hypertensive injury, not classic diabetic nephropathy, consistent with previous reports [8,40]. An injury versus pressure plot, such as Fig.…”

Section: Discussionsupporting

confidence: 77%

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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Section: Discussionsupporting

confidence: 77%

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

et al. 2012

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“…Second, our animals were not hypertensive. The presence of systemic hypertension exacerbates most forms of kidney disease and does interact with hyperglycaemia to induce greater structural damage [43,44]. Although frank systemic hypertension is not a feature of early human diabetic nephropathy, it is possible that with the addition of a third insult, hypertension, LPD diabetic animals may have more rapidly progressive renal disease than NPD animals.…”

Section: Discussionmentioning

confidence: 99%

The effect of intrauterine environment and low glomerular number on the histological changes in diabetic glomerulosclerosis

et al. 2005

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Aims/hypothesis: We tested the hypothesis that diabetic glomerulosclerosis would develop more rapidly in animals with fewer glomeruli. Methods: We studied the female offspring of Wistar rats that had been fed a low-protein diet (LPD) containing 6% protein or a normal-protein diet (NPD) containing 18% protein during pregnancy. Streptozotocin diabetes was induced at 12 weeks and animals were killed at 40 weeks. Results: Non-diabetic LPD offspring were of lower birthweight than the NPD offspring (5.19± 0.64 vs 6.45±0.67 g, p<0.001) and had fewer glomeruli (27,402±3,137 vs 34,203±6,471, p<0.05). Glomerular volume correlated inversely with glomerular number (r=−0.64, p=0.035), but total glomerular filtration surface area was reduced in the LPD animals (4,770±541 vs 5,779±1,302 mm 2 , p=0.05). Other renal structural and functional parameters were similar. In LPD and NPD diabetic animals, glomerular volume and basement membrane width were significantly increased compared to their respective controls. Podocyte density was lowest in the LPD diabetic animals (not significant), and the area covered by each podocyte was greater in the LPD diabetic group (2.40±0.693 ×10 −3 mm 2 ) than in the LPD control group (1.68±0.374 ×10 −3 mm 2 , p<0.001) and in the NPD diabetic animals (1.71±0.291 ×10 −3 mm 2 , p<0.05). There was no difference in any other structural or functional parameter between the LPD and NPD diabetic animals. Conclusions/ interpretation: A decrease in glomerular number was not deleterious to renal structure and function over 40 weeks in this animal model. Further work in models with progressive renal impairment and hypertension is necessary to clarify the impact of glomerular number on the development of renal disease.

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“…PCNA is one of the proteins involved in cell proliferation and DNA synthesis, and an increase in PCNA expression is a marker of glomerular sclerosis and tubulointerstitial injury. In addition, the expression of desmin as a marker of podocyte injury [23][24][25] was significantly increased in the vehicle-treated SHR/NDmcr-cp group than in the WKY/Izm group. Previous studies have shown that podocyte damage is an early event leading to glomerulosclerosis and tubulointerstitial damage in Zucker obese rats with type II diabetes mellitus.…”

Section: Discussionmentioning

confidence: 99%

Renoprotective effects of an angiotensin II receptor blocker in experimental model rats with hypertension and metabolic disorders

et al. 2009

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Metabolic syndrome (MS) is an independent risk factor for chronic kidney diseases. As the renin-angiotensin system (RAS) is known to have a key role in renal damage, blockade of RAS may show renoprotective effects in MS. In this study, we investigated the renoprotective effects and mechanisms of action of an angiotensin receptor blocker (ARB) in spontaneously hypertensive (SHR/NDmcr-cp) rats as a model of MS. Male SHR/NDmcr-cp rats at 9 weeks of age were divided into three groups, each of which was treated for 12 weeks with vehicle, hydralazine (7.5 mg kg À1 per day, p.o.) or ARB (olmesartan, 5 mg kg À1 per day, p.o.). Blood pressure and urinary protein (UP) excretion were monitored. Kidney tissues were subjected to histological, immunohistochemical and molecular analyses. UP excretion increased with age in vehicle-treated SHR/NDmcr-cp rats compared with that in age-matched WKY/Izm rats. In addition, there was significant glomerular damage (increased glomerular sclerosis index, desmin staining and proliferating cell nuclear antigen (PCNA)-positive cells, electron microscopic findings of podocyte injury) and tubulointerstitial damage (increased tubulointerstitial fibrosis index, type IV collagen staining, PCNA-positive cells and expression of TGF-b mRNA) in vehicle-treated SHR/NDmcr-cp rats compared with that in control rats. All the findings that related to glomerular and tubulointerstitial damage were significantly improved by ARB. Hydralazine mitigated the observed renal damage but was much less effective than ARB, despite similar decreases in blood pressure. There were no significant differences in glucose and lipid metabolism among vehicle-treated, hydralazine-treated and ARB-treated SHR/NDmcr-cp animals. These data suggest that RAS is deeply involved in the pathogenesis of renal damage in MS, and ARBs could provide a powerful renoprotective regimen for patients with MS.

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Hypertension superimposed on type II diabetes in Goto Kakizaki rats induces progressive nephropathy

Cited by 77 publications

References 41 publications

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

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

The effect of intrauterine environment and low glomerular number on the histological changes in diabetic glomerulosclerosis

Renoprotective effects of an angiotensin II receptor blocker in experimental model rats with hypertension and metabolic disorders

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