Inhibition of neuronal nitric oxide synthase ameliorates renal hyperfiltration in streptozotocin-induced diabetic rat

Ito, Aki; Uriu, Kohei; Inada, Y; Qie, Yue-Ling; Takagi, Ichiro; Ikeda, Masanori; Hashimoto, Osamu; Suzuka, Kanako; Eto, Sumiya; Tanaka, Yoshiya; Kaizu, Kazo

doi:10.1067/mlc.2001.116843

Cited by 33 publications

(35 citation statements)

References 29 publications

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“…In the current study, the reductions in fractional excretion of calcium and magnesium occurred despite a concurrent increase in GFR in OD rats. Renal hyperfiltration is widely reported in diabetic rats; suggested mechanisms include glucosuria-mediated osmotic diuresis (25), a reduction in tubuloglomerular feedback (26), increased glomerular arginine uptake (27), increased nitric oxide generation (28), and renal sympathetic nerve activity (29). These mechanisms have not been explored in OD rats, so the reason(s) for the increase in GFR observed in OD in the current study remains unclear.…”

Section: Discussionmentioning

confidence: 43%

Increased Renal Tubular Reabsorption of Calcium and Magnesium by the Offspring of Diabetic Rat Pregnancy

et al. 2005

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Diabetic pregnancy has a marked influence on offspring calcium and magnesium homeostasis. Urinary excretion of calcium and magnesium is reduced, yet offspring of diabetic pregnancy exhibit hypomagnesemia and hypocalcemia. The aim of this study was to measure renal hemodynamic and tubular function in the offspring of diabetic (OD) and control, nondiabetic (OC) rats at 4 and 8 wk of age to determine the glomerular and tubular mechanisms through which renal calcium and magnesium handling are programmed in utero. The fraction of filtered calcium that was excreted was significantly lower in OD at both 4 and 8 wk of age [8 wk: OC (n ϭ 6), 11.8 Ϯ 2.9 versus OD (n ϭ 5), 4.3 Ϯ 0.6%; p Ͻ 0.05] and that of magnesium was lower at 8 wk of age [OC (n ϭ 6), 42.4 Ϯ 7.5 versus OD (n ϭ 5), 13.0 Ϯ 1.7%; p Ͻ 0.01]. This increased reabsorption occurred despite an elevated GFR in OD. These findings clearly indicate that tubular reabsorptive mechanisms for calcium and magnesium are increased markedly in OD. Serum PTH concentration was reduced in 8-wk-old OD [OC (n ϭ 7), 539.4 Ϯ 142.1 versus OD (n ϭ 9), 174.3 Ϯ 69.4 pg/ml; p Ͻ 0.05], consistent with previous reports in human infants. Taken together, these observations suggest that the basis for the altered renal magnesium and calcium handling in OD involves increased tubular transport activity and possibly increased sensitivity of these mechanisms to PTH. Diabetic pregnancy has a marked impact on maternal calcium and magnesium homeostasis in both humans and rats. Hypomagnesemia has been widely reported in human diabetic pregnancy (1-3), and diabetic pregnant rats display a marked increase in urinary magnesium excretion (4,5). A reduction in third-trimester plasma calcium concentration has been observed in human diabetic pregnancy in one study (3), but the majority of studies have found no difference in calcium concentrations between normal and diabetic pregnancies. However, in the diabetic rat, pregnancy is associated with marked increases in urinary calcium (4,5) and hypocalcemia in some (4) but not all studies (6).These changes in maternal divalent ion handling have a profound impact on the developing fetus. Human offspring of diabetic pregnancy exhibit hypomagnesemia and hypocalcemia as neonates (2,7-9). In the rat, renal handling of calcium and magnesium is also altered in the offspring of streptozotocin (STZ)-treated diabetic rats (OD). We recently reported that OD retain both calcium and magnesium as neonates and that this continues into adulthood (10). These changes in divalent ion homeostasis also occur in conjunction with changes in bone structure. Human offspring of diabetic pregnancy are susceptible to congenital malformations, including skeletal abnormalities (11), and have lower bone mineral content (12). Reduced bone mineral content and abnormal skeletal development have also been observed in the offspring of STZ-treated diabetic rat mothers (13,14). We recently extended these observations and showed that offspring of STZ-treated diabetic rats have reduced trabecular and ...

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Section: Discussionmentioning

confidence: 43%

Increased Renal Tubular Reabsorption of Calcium and Magnesium by the Offspring of Diabetic Rat Pregnancy

et al. 2005

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“…11 The DL rats in the present study showed a similar GFR response, and we hypothesize this is because nitric oxide synthesis was blocked. Indeed, other studies in humans and animals also have shown that nitric oxide may play an important role in diabetic hyperfiltration, 9,[25][26][27][28][29][30] although this is somewhat controversial and perhaps dependent on the period of diabetes in which the studies are conducted. Figure 4 shows in addition that the DL rats did not lose as much sodium during the initial stages of diabetes.…”

Section: Brands Et Al Superoxide and Hypertension In Diabetesmentioning

confidence: 99%

“…1,2,5,8,9,23 The latter mechanism fits with the evidence that nitric oxide production may be increased in diabetes, at least in the early stages, but that its vasodilator action can be suppressed below normal as the result of superoxide. 1,2,4,5,8,9 However, there also is evidence that nitric oxide activity in the cardiovascular system is enhanced as well, 9,[25][26][27][28][29][30] and an important consideration probably is the duration of diabetes at the time of testing. 9,10 Consistent with that, we have reported that endotheliummediated dilation is not impaired at the onset of type I diabetes.…”

Section: Brands Et Al Superoxide and Hypertension In Diabetesmentioning

confidence: 99%

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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“…Hyperglycemia and hyperinsulinemia are exhibited in the early phases of the disease as a result of islet cell hyperplasia and peripheral insulin resistance, and 38-week-old OLETF rats are used as a model of human type 2 diabetes mellitus [15][16][17][18] . With continued aging, the rats eventually develop hypoinsulinemia as a result of the deterioration of islet beta cells 16,18 , and the plasma insulin level in OLETF rats over 60 weeks of age is lower than that in Long-Evans rats of the corresponding age used as normal controls 19,20 . The changes in the biological characteristics of OLETF rats show an obvious correspondence to those that take place in human type 2 diabetes mellitus.…”

Section: Introductionmentioning

confidence: 99%

Kinetic Analysis of the Rate of Corneal Wound Healing in Otsuka Long-Evans Tokushima Fatty Rats, a Model of Type 2 Diabetes Mellitus

et al. 2010

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Diabetic keratopathy is a well-known ocular complication secondary to type 2 diabetes mellitus. In this study, we performed a kinetic analysis of corneal wound healing in Long-Evans rats (normal rat) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus. Corneal wound healing in 7-week-old normal rats was mostly complete 24 h after corneal epithelial abrasion, and the process of corneal wound healing took place according to an equation with a fi rst-order rate constant. The rate of corneal wound healing in normal rats decreased with aging. The process of corneal wound healing in 38-and 60-week-old normal and OLETF rats occurred in two phases with rate constants for the fi rst and second phases represented as α and β, respectively. The α and β values in 38-and 60-week-old OLETF rats were lower than those in normal rats of the corresponding age. Furthermore, a close relationship was observed between the corneal wound healing rate constant and plasma glucose levels in OLETF rats. The present studies suggest the sequence of events that occur following damage to the corneal surface in OLETF rats as a model animal for a human type 2 diabetes mellitus.

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Inhibition of neuronal nitric oxide synthase ameliorates renal hyperfiltration in streptozotocin-induced diabetic rat

Cited by 33 publications

References 29 publications

Increased Renal Tubular Reabsorption of Calcium and Magnesium by the Offspring of Diabetic Rat Pregnancy

Increased Renal Tubular Reabsorption of Calcium and Magnesium by the Offspring of Diabetic Rat Pregnancy

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

Kinetic Analysis of the Rate of Corneal Wound Healing in Otsuka Long-Evans Tokushima Fatty Rats, a Model of Type 2 Diabetes Mellitus

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