Biphasic Alteration of Renin-Angiotensin-Aldosterone System in Streptozotocin-Diabetic Rats

Kikkawa, Ryuichi; Kitamura, Eisaku; Fujiwara, Yoshihiko; Haneda, Masakazu; Shigeta, Yukio

doi:10.1159/000173083

Cited by 21 publications

(19 citation statements)

References 11 publications

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“…Reports of an elevated PRA (30) contrast with others reporting reduced PRA in patients with type 1 diabetes (31). A study with STZ-treated rats showed a reduction of PRA after 4 wk (32), whereas an older study observed a biphasic reaction with an increase in the first week followed by a reduction of PRA until week 8 (33). Our results show a highly significant reduction of circulating renin only in the ETBRd-STZ group.…”

Section: Discussioncontrasting

confidence: 46%

Diabetic Endothelin B Receptor–Deficient Rats Develop Severe Hypertension and Progressive Renal Failure

Pfab¹,

Thöne-Reineke²,

Theilig³

et al. 2006

Journal of the American Society of Nephrology

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The endothelin (ET) system has been implicated in the pathogenesis of diabetic nephropathy. The role of the ET-B receptor (ETBR) is still unclear. The effect of ETBR deficiency on the progression of diabetic nephropathy in a streptozotocin model was analyzed in four groups: (1) Homozygous ETBR-deficient (ETBRd) diabetic rats, (2) ETBRd rats, (3) diabetic controls, and (4) wild-type controls. BP and kidney function were measured for 10 wk, followed by biochemical and histologic analysis of the kidneys. The study demonstrates that ETBRd diabetic rats on a normal-sodium diet develop severe hypertension, albuminuria, and a mild reduction of creatinine clearance. The strong BP rise seems not to be caused by activation of the renin-angiotensin-aldosterone system or by suppression of the nitric oxide system. Elevated plasma ET-1, possibly reflecting a reduced ETBR-dependent clearance, seems to cause the severe hypertension via the ETA receptor. The results do not support the hypothesis that a reduction of ETBR activity inhibits the progression of diabetic nephropathy. The study demonstrates for the first time that the combination of diabetes and ETBR deficiency causes severe low-renin hypertension with progressive renal failure. D iabetic nephropathy is the leading and most costly cause of ESRD and dialysis treatment in industrialized countries (1,2). Strategies to stop its progression are still not effective enough. The endothelin (ET) system might be an interesting novel target for the treatment of diabetic nephropathy (3-6). Besides their potent vasoconstrictive properties, ET are profibrotic-acting paracrine hormones, especially in the kidney (7). The ET system seems to be particularly important for the pathogenesis of diabetic nephropathy: (1) The renal ET system is activated in patients with diabetic nephropathy as well as in animal models of diabetes-induced kidney damage (8 -10), (2) a primary activated renal ET system causes kidney fibrosis in ET-1 transgenic mice (7,11) as well as in ET-2 transgenic rats (12), and (3) blocking the ET system using ET-A receptor (ETAR) or combined ETAR/ETBR antagonists improves protein and albumin excretion and reduces pathologic matrix protein synthesis in diabetic animals in a BP-independent manner (3-6).There is evidence that the ETBR might play a role in remodeling processes of the kidney (13). This led us to the hypothesis that reduction of ETBR activity might be protective against diabetic nephropathy. A widely used ETBR-deficient (ETBRd) rat model, developed by the group of Yanagisawa (14 -16), served as a tool to test this hypothesis. In this study, we analyzed the effect of ETBR deficiency on the progression of diabetic nephropathy in rats with streptozotocin (STZ)-induced diabetes. Materials and Methods Animals and Study ProtocolETBRd rats (ETBRsl/sl) and wild-type (WT) controls were provided by Yanagisawa (16). All animal experiments were conducted in accordance with local institutional guidelines for the care and use of laboratory animals. Genotyping was accomplishe...

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Section: Discussioncontrasting

confidence: 46%

Diabetic Endothelin B Receptor–Deficient Rats Develop Severe Hypertension and Progressive Renal Failure

Pfab¹,

Thöne-Reineke²,

Theilig³

et al. 2006

Journal of the American Society of Nephrology

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“…We 14 and others 40 have shown that PRA increases significantly during the first week of diabetes, and chronic L-NAME treatment amplifies and prolongs that response. 11 We have a working hypothesis that an increase in GFR under these conditions actually is required to keep blood pressure from increasing.…”

Section: Perspectivesmentioning

confidence: 68%

Nitric Oxide May Prevent Hypertension Early in Diabetes by Counteracting Renal Actions of Superoxide

2004

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Abstract-The dependence of blood pressure on a balance between superoxide and nitric oxide may be amplified in diabetes. We have shown that the first occurrence of sustained hyperglycemia in type I diabetes causes hypertension when induced in rats that have had nitric oxide synthesis blocked chronically (L-NAME, 10 g/kg per minute IV). This study used tempol (18 mol/kg per hour IV) to test the hypothesis that superoxide mediates that hypertensive response. Induction of diabetes in untreated rats had no significant effect on mean arterial pressure (MAP, measured 18 h/d), and glomerular filtration rate (GFR) increased significantly during the 2 weeks of diabetes. Chronic infusion of L-NAME in a separate group of rats increased baseline MAP from Ϸ90 mm Hg to a stable level of Ϸ120 mm Hg after 6 days of infusion, and induction of diabetes (streptozotocin, 40 mg/kg IV) in those rats caused a rapid, progressive increase in MAP that averaged 156Ϯ5 mm Hg by day 14 of diabetes that was associated with a decrease in GFR and 4-fold increase in isoprostane excretion. Tempol infusion was begun on day 2 of diabetes in a subgroup of those rats, and the progressive hypertensive response was prevented, with MAP averaging 134Ϯ10 mm Hg by day 14. In addition, the normal renal hyperfiltration response was restored by tempol and the increase in isoprostane did not occur. Thus, the hypertension and decrease in GFR caused by onset of diabetes in rats without a functioning nitric oxide system was prevented by chronic administration of the superoxide dismutase mimetic tempol. Key Words: blood pressure Ⅲ glomerular filtration rate Ⅲ diabetes mellitus Ⅲ nitric oxide Ⅲ L-NAME T here is good evidence for opposing actions of superoxide and nitric oxide in the chronic control of arterial pressure under physiological and pathophysiologic states.1-9 Most of this evidence suggests that there is a balance between the blood pressure-lowering effects of nitric oxide and the hypertensive actions of superoxide that involves direct and indirect chemical interaction as well as physiological interaction at effector sites. Shifts in that balance can have wide-ranging effects, and there could be a more critical and tenuous balance between the two in the control of blood pressure in diabetes because of the neurohumoral and direct effects of hyperglycemia and the added stress imparted by renal fluid and electrolyte losses caused by poor glycemic control. Studying the interaction between nitric oxide and superoxide has been complicated, however, by evidence that production of both may be increased in diabetes 1,2,5,8,9 but that nitric oxide synthesis becomes impaired over time. 9,10 We recently tested the hypothesis that nitric oxide was critical for preventing hypertension very early in diabetes. 11,12 This was based on our previous work that suggested endothelium-dependent vasodilation was not impaired during the first week of type I diabetes 13 and that angiotensin (Ang) II increased significantly during that same period. 14 We found that blocking nitric ...

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“…34 Indeed, it was demonstrated that STZ-diabetic rats (2 weeks) have elevated plasma levels of angiotensin II under basal conditions. 38 It was described that the angiotensin II system is involved with the increase of sympathetic outflow by its action on the central nervous system. It is possible that the larger increase in AP observed in our study after SAD in the diabetic rats is associated with an increased baseline-activated renin-angiotensin system.…”

Section: Protocol 2: Volume Expansionmentioning

confidence: 99%

Cardiopulmonary Reflex Impairment in Experimental Diabetes in Rats

et al. 1999

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The aim of the present study was to evaluate the sensitivity of the cardiopulmonary receptors in experimental diabetes induced by streptozotocin by the use of 2 different methods: (1) administration of increasing doses of serotonin to analyze peak changes of arterial pressure and heart rate for each given dose in conscious intact normal and diabetic rats; (2) expanding blood volume with the use of dextran (6%) to produce similar increases in left ventricular end-diastolic pressure to quantify the arterial pressure, heart rate, and renal sympathetic nerve activity in sinoaortic, denervated, anesthetized normal and diabetic rats. Blood samples were collected to measure blood glucose. Diabetic rats showed hyperglycemia (220.7 versus 70.2 mmol/L), reduced body weight (22612 versus 2604 g) and heart rate (29414 versus 35010 bpm), and similar arterial pressure (1044 versus 1134 mm Hg) when compared with control rats. Serotonin induced significant bradycardia and hypotension, which were similar and proportional to the dose injected in both groups. Mean arterial pressure and heart rate decreases in response to volume overload were significantly lower in diabetic than in control rats. The reflex reduction of the renal sympathetic nerve activity as expressed by percentage changes in nerve activity in response to increasing left end-diastolic pressure was abolished in diabetic animals (1.90.8% versus 144%/mm Hg in controls). These results showed an impairment of cardiopul-monary reflex control of circulation in diabetes during acute volume expansion. The normal responses to serotonin administration indicated that the cardiopulmonary reflex is still preserved in diabetic rats. (Hypertension. 1999;34[part 2]:813-817.) Key Words: cardiac function diabetes mellitus blood pressure renal nerve reflex C linical studies indicate that insulin-dependent diabetes mellitus is associated with alterations of the autonomic nervous system control of cardiovascular function. Beat-to-beat heart rate (HR) variation is reduced at rest and during deep breathing, suggesting that parasympathetic nervous control of the heart is diminished in diabetics. 1,2 On the other hand, a blunted chronotropic response to exercise and sub-normal plasma catecholamine levels 3 suggest an impairment of sympathetic activity in these individuals. 4 In experimental studies, administration of streptozotocin (STZ) is a well-established method for the induction of diabetes in rats. This model has been commonly used to demonstrate the occurrence and to study the pathogenic mechanisms of various complications such as changes in fluid balance and blood volume homeostasis. 5 Recent results from our laboratory suggested that reflex tachycardic response elicited by the reduction of arterial pressure (AP) is attenuated in short-term diabetes, 6 whereas the reflex bradycardia in response to an AP increase has been reported to be normal. In contrast, baroreflex-mediated bra-dycardia is impaired in alloxan-induced diabetic rabbits, suggesting that changes in baroreflex function...

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Biphasic Alteration of Renin-Angiotensin-Aldosterone System in Streptozotocin-Diabetic Rats

Cited by 21 publications

References 11 publications

Diabetic Endothelin B Receptor–Deficient Rats Develop Severe Hypertension and Progressive Renal Failure

Diabetic Endothelin B Receptor–Deficient Rats Develop Severe Hypertension and Progressive Renal Failure

Nitric Oxide May Prevent Hypertension Early in Diabetes by Counteracting Renal Actions of Superoxide

Cardiopulmonary Reflex Impairment in Experimental Diabetes in Rats

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