Genetic Hypertension Accelerates Nephropathy in the Streptozotocin Diabetic Rat

Cooper, Mark E.; Allen, Terri J.; Macmillan, Pauline A.; Bach, Leon Ashley; Jerums, George; Doyle, A. E.

doi:10.1093/ajh/1.1.5

Cited by 57 publications

(40 citation statements)

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“…In diabetic SHR the ACE inhibitor enalapril attenuated but did not normalize progression of albuminuria. 37 In the study of Lewis and coworkers, 38 renal impairment still progressed in patients with diabetic nephropathy, especially if hypertensive, despite partial renoprotection observed in captopril-treated patients. The available data suggest that strict control of blood pressure is essential to confer the full renal and cardioprotective effects of antihypertensive drugs.…”

Section: Discussionmentioning

confidence: 99%

Dual Inhibition of Neutral Endopeptidase and Angiotensin-Converting Enzyme in Rats With Hypertension and Diabetes Mellitus

Tikkanen

Rockell

et al. 1998

Hypertension

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Abstract-It has been suggested that combined inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) may lower blood pressure more effectively than either treatment alone, independent of the degree of salt and volume status or the activity of the renin-angiotensin system. The effects of NEP inhibition in hypertension associated with diabetes mellitus are largely unknown. We therefore compared ACE inhibition, NEP inhibition, and dual NEP/ACE inhibition in diabetic hypertensive rats. Spontaneously hypertensive rats (SHR) aged 9 to 10 weeks were injected with either streptozotocin (45 mg/kg) or citrate buffer and randomized to receive either the ACE inhibitor captopril (25 mg/kg BID), the NEP inhibitor SCH 42495 (30 mg/kg BID), the dual NEP/ACE inhibitor S 21402 (25 or 50 mg/kg BID), or vehicle by gavage for 4 weeks. A group of diabetic SHR was also allocated to receive the combination of SCH 42495 (30 mg/kg BID) and captopril (25 mg/kg BID). The degree of renal NEP inhibition was determined by autoradiography, and plasma renin activity (PRA) was determined by radioimmunoassay. In diabetic SHR, the dual NEP/ACE inhibitor (50 mg/kg BID), as well as the combination of the NEP inhibitor and the ACE inhibitor, reduced systolic blood pressure more effectively than the ACE inhibitor (PϽ0.001) or the NEP inhibitor (PϽ0.001) alone. In nondiabetic SHR, the dual NEP/ACE inhibitor and the ACE inhibitor were equally effective, while the NEP inhibitor had only slight blood pressure-lowering effects. Relative heart weight decreased in parallel to the changes in blood pressure. Renal NEP was clearly inhibited (70% to 92%; PϽ0.001) by both the NEP inhibitor and the dual NEP/ACE inhibitor. Both the ACE inhibitor and the dual NEP/ACE inhibitor increased PRA, but the stimulating effect of dual NEP/ACE inhibition on PRA was less than that observed with ACE inhibition alone (PϽ0.05). Albuminuria in diabetic SHR was lower during treatment with both the dual NEP/ACE inhibitor (50 mg/kg BID) and the combination of NEP inhibition and ACE inhibition compared with vehicle treatment (PϽ0.05). In conclusion, the present study shows that hypertension in SHR with streptozotocin-induced diabetes is modulated by natriuretic peptides and thus is sensitive to NEP inhibition. The increased efficacy of dual NEP/ACE inhibition on blood pressure in diabetic SHR, compared with ACE or NEP inhibition alone, suggests that this therapeutic approach may prove beneficial in the treatment of hypertension associated with diabetes mellitus and other forms of volume-dependent hypertension.(Hypertension. 1998;32:778-785.)Key Words: natriuretic peptides Ⅲ angiotensin Ⅲ renal circulation Ⅲ albuminuria Ⅲ blood pressure I nhibitors of angiotensin-converting enzyme (ACE) have proved effective in the treatment of hypertension associated with diabetes mellitus. As shown in a meta-analysis of clinical trials, ACE inhibitors reduce proteinuria and attenuate progression of renal failure in patients with diabetic nephropathy more effectively than tre...

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Section: Discussionmentioning

confidence: 99%

Dual Inhibition of Neutral Endopeptidase and Angiotensin-Converting Enzyme in Rats With Hypertension and Diabetes Mellitus

Tikkanen

Rockell

et al. 1998

Hypertension

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“…28 The development of diabetic renal injury was accelerated by uninephrectomy, which has been shown to increase glomerular capillary hydraulic pressure and plasma flow rate in nondiabetic rats. 29 This study confirmed that in SHR a high salt intake prevents the hypotensive effect of chronic ACE inhibitor therapy.…”

Section: Discussionmentioning

confidence: 99%

Salt blocks the renal benefits of ramipril in diabetic hypertensive rats.

1991

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To establish if the benefit of angiotensin converting enzyme inhibitor therapy in retarding progressive diabetic renal injury is due to a specific intrarenal effect or the systemic hypotensive effect, we studied the effect of long-term ramipril treatment on blood pressure, glomerular filtration rate, and urinary protein excretion in streptozotocin-diabetic spontaneously hypertensive rats. The hypotensive effect of ramipril was prevented by a high salt diet, which did not alter the degree of renal angiotensin converting enzyme inhibition. Three weeks after uninephrectomy and induction of diabetes, rats were allocated to three groups. Groups 1 and 2 were given 1% NaCl, whereas group 3 was given water as drinking solution. One week later, groups 2 and 3 received 0.4 mg/kg/day ramipril in their drinking solution, which was continued over a 2-month period. Ramipril produced a blood pressure fall only in water-drinking rats (group 3) despite a similar reduction in plasma and renal angiotensin converting enzyme activity in groups 2 and 3. Salt-loaded rats had a progressive increase in urinary protein excretion over the duration of study. Ramipril treatment prevented an increase in protein excretion only in animals given water and with a reduced systolic blood pressure. Glomerular nitration rate was similar in all three groups. Ramipril treatment improved animal survival independently of a reduction in blood pressure or an effect on proteinuria. Although it is possible that angiotensin converting enzyme inhibitors have specific intrarenal effects reducing progression of diabetic proteinuria, concomitant control of systemic blood pressure appears to be necessary to demonstrate a benefit. (Hypertension 1991;17:497-503) U ncontrolled systemic hypertension is a wellknown cause of progressive renal injury in both humans and experimental animals. 1Hypertension is commonly associated with diabetic renal disease,'-3 and it has been shown to accelerate the rate of development of diabetic nephropathy both in humans 4 and in streptozotocin-diabetic rats. 13 or in other renal disorders. 1415 However, it is difficult to determine from these studies if the beneficial effect of ACE Received February 9, 1990; accepted in revised form November 29, 1990. inhibitors was due to a specific intrarenal effect of ACE inhibition or due to their systemic hypotensive effect.To evaluate this question further, we examined the effect of long-term administration of the ACE inhibitor ramipril on blood pressure, glomerular filtration rate, and proteinuria in streptozotocin diabetic uninephrectomized spontaneously hypertensive rats (SHR). To prevent the hypotensive effect of ACE inhibition, the rats were maintained on a high salt diet, which is known to oppose the blood pressurelowering action of ACE inhibitors. -17 Methods Study Protocol

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“…The functional and structural characteristics of this diabetic nephropathy model were fully described previously [17]. Indeed, Righetti et al [18] recently demonstrated an earlier accumulation of cortical renal fibronectin, a matrix protein implicated in renal glomerulosclerosis, in diabetic SHR as compared with diabetic control rats.…”

Section: Introductionmentioning

confidence: 86%

Increased Urinary TGF-β1 and Cortical Renal GLUT1 and GLUT2 Levels: Additive Effects of Hypertension and Diabetes

et al. 2005

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Background/Aim: Diabetes and mesangial stretch caused by hypertension increase mesangial matrix deposition which is induced by local production of transforming growth factor beta 1 (TGF-β1). Both conditions are associated with cortical GLUT1 overexpression. We evaluated the effect of genetically determined hypertension and its association with diabetes on urinary TGF-β1 and cortical GLUT1 and GLUT2 expression. Methods: We studied Wistar-Kyoto rats (controls, C) and spontaneously hypertensive rats (SHR), weighing ∼210 g, 30 days after the injection of streptozotocin (diabetic, D) or citrate buffer (10 C, 9 SHR, 12 C-D and 15 SHR-D). Twenty-four-hour urine was collected for glucose, albumin, and TGF-β1 determinations. Catheters were implanted into the femoral artery to measure the arterial blood pressure in conscious animals 1 day later. Then GLUT1 and GLUT2 protein levels (Western blotting) in renal cortex and medulla were evaluated. Results: The cortical GLUT1 levels were 5, 2, and 7 times higher in SHR, C-D, and SHR-D groups versus C group (p < 0.05); the GLUT2 contents were 1.5, 1.8, and 2.3 times higher in SHR, C-D and SHR-D groups versus C group (p < 0.05). The urinary TGF-β1 level was elevated by diabetes and diabetes and hypertension, but not by hypertension alone: 1.39 ± 0.2, 2.34 ± 0.6, 18.2 ± 3.2, and 28.8 ± 7.6 ng/24 h, respectively, in C, SHR, C-D, and SHR-D groups (p < 0.05). Conclusions: Diabetes, hypertension, and especially their association increase the renal cortical GLUT1 and GLUT2 levels. The magnitude of GLUT1 overexpression caused by hypertension is higher than that induced by diabetes alone. The impact on urinary TGF-β1 occurs when diabetes and hypertension are associated, suggesting an effect that is triggered in the presence of GLUT1 overexpression and hyperglycemia.

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Genetic Hypertension Accelerates Nephropathy in the Streptozotocin Diabetic Rat

Cited by 57 publications

References 0 publications

Dual Inhibition of Neutral Endopeptidase and Angiotensin-Converting Enzyme in Rats With Hypertension and Diabetes Mellitus

Dual Inhibition of Neutral Endopeptidase and Angiotensin-Converting Enzyme in Rats With Hypertension and Diabetes Mellitus

Salt blocks the renal benefits of ramipril in diabetic hypertensive rats.

Increased Urinary TGF-β1 and Cortical Renal GLUT1 and GLUT2 Levels: Additive Effects of Hypertension and Diabetes

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