Upregulation of hypothalamic nitric oxide synthase gene expression in streptozotocin-induced diabetic rats

Serino, Ryota; Ueta, Yoichi; Tokunaga, Masaki; Hara, Yuko; Nomura, Masayoshi; Kabashima, Narutoshi; Shibuya, Izumi; Hattori, Yukio; Yamashita, Hiroshi

doi:10.1007/s001250050962

Cited by 50 publications

(21 citation statements)

References 33 publications

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“…It has been reported that expression of nNOS gene in the hypothalamic paraventricular and supraoptic nuclei is increased by osmotic stimuli such as dehydration and salt loading [35,36]. More recently, upregulation of hypothalamic nNOS gene was also found in experimental diabetic rats and it is suggested that this increase is caused by plasma hyperosmolality and hyperglycaemia [37]. All these findings allow us to hypothesize that increased vasopressin or plasma hyperosmolality possibly stimulates renal nitric oxide synthesis in diabetic rats.…”

Section: Discussionmentioning

confidence: 84%

Neuronal and endothelial nitric oxide synthase expression in outer medulla of streptozotocin-induced diabetic rat kidney

et al. 2000

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Several studies have shown that the intrarenal synthesis of vasodilators, including prostaglandin [1], kinin [2] and atrial natriuretic peptide (ANP) [3], are increased in diabetic rats and it has been proposed that this increase is responsible for the glomerular hyperfiltration in such rats. Similarly, increased renal nitric oxide (NO) activity, as assessed by urinary excretion of nitrites and nitrates, has also been reported in experimental diabetes [4±9]. Apart from the measurement of urinary nitrite/nitrate (NO 2 ± /NO 3 ± ) concentrations, very little is known about the levels of NO synthase (NOS) mRNA or protein in the kidney of diabetic rats. An increase of endothelial NO syn- Diabetologia (2000) Abstract Aims/hypothesis. Several investigations have shown that the renal medulla has a greater capacity to generate nitric oxide than the renal cortex. To further evaluate the changes of nitric oxide synthesis in the kidney, particularly in the outer medulla, in disorders involving fluid and electrolyte imbalances, we sought to determine renal nitric oxide synthase expression in the diabetic rats. Methods. We determined renal nitric oxide synthase mRNA and urinary nitrite/nitrate excretion in 12 normal and 12 streptozotocin-induced diabetic rats by reverse transcription-polymerase chain reaction with Southern blot hybridization and with Griess reaction, respectively. Nitric oxide synthase immunoreactivity was detected by immunohistochemistry in four normal and four diabetic rats.Results. Neuronal and endothelial nitric oxide synthase mRNA were 3.5-fold and 1.8-fold increased in the outer medulla of 12 diabetic rats with no difference found in the cortex and inner medulla when compared with 12 normal rats. Urinary nitrite/nitrate excretion was significantly increased from the first week after diabetic induction. In normal rats, immunohistochemical studies showed positive neuronal and endothelial nitric oxide synthase immunostaining in almost all segments of renal tubules. Diabetic rats had the greatest enhancement of immunostaining for neuronal and endothelial nitric oxide synthase in the proximal straight tubule and medullary thick ascending limb. Conclusion/interpretation. Our results indicate that increases in neuronal and endothelial nitric oxide synthase synthesis in the kidney, particularly in the outer medulla, possibly play an important part in the adaptation of renal function to hyperglycaemia and hyperosmolality in diabetes. [Diabetologia (2000) 43: 649±659]

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Section: Discussionmentioning

confidence: 84%

Neuronal and endothelial nitric oxide synthase expression in outer medulla of streptozotocin-induced diabetic rat kidney

et al. 2000

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“…Two other studies explored nNOS expression in extrarenal neuronal tissue in diabetes. Serino et al [32] found increased hypothalamic nNOS gene expression in STZ-diabetic rats, and normalization of nNOS expression by insulin treatment. Roufail et al [33] found decreased nNOS protein expression and activity in the retinal neurons of diabetic rats.…”

Section: Discussionmentioning

confidence: 99%

Role of Renal Nitric Oxide Synthase in Diabetic Kidney Disease during the Chronic Phase of Diabetes

Khamaisi¹,

Keynan²,

Bursztyn³

et al. 2006

Nephron Physiol

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Background: Several studies have suggested that an early increase in renal nitric oxide (NO) production or activity mediates pathophysiologic and morphologic changes in diabetic nephropathy. To evaluate the role of NO in developing diabetic kidney disease, we studied the NO system in streptozotocin (STZ)-induced diabetic rats for a period of 8 weeks. Methods: Control rats, STZ-induced diabetic rats, and STZ-induced diabetic rats treated with insulin were monitored and sacrificed at 1, 2, and 8 weeks. Urinary cGMP was measured, and the levels and activity of NO synthase (NOS) isoforms in the kidney cortex were determined at specific times by immunoblotting and diaphorase staining. Results: Diabetic rats had increased kidney weight, urinary volume, glucose, sodium and potassium excretion, which was precluded by insulin treatment. Creatinine clearance was increased in the diabetic group and reversed by insulin treatment. Urinary cGMP decreased by 71, 93, and 92% at 1, 2, and 8 weeks of diabetes, respectively, compared with the control animals. Insulin treatment curtailed the urinary cGMP reduction in diabetic animals. Total NOS activity in the renal cortex was reduced by 65, 52, and 44% after 1, 2, and 8 weeks of diabetes, respectively, and returned to normal levels upon insulin treatment. NADPH diaphorase staining of renal cortical slices showed a 77, 63, and 70% decrease in neuronal NOS isoform activity in the macula densa after 1, 2, and 8 weeks of diabetes, respectively, compared with control non-diabetic animals. This reduction was normalized by insulin treatment. Endothelial NOS protein expression in the kidney cortex tended to increase after 1 week of diabetes and its level was elevated significantly after 2 and 8 weeks of diabetes. However, neuronal NOS protein expression in the kidney cortex was reduced by 52% in 2-week diabetic animals, but this reduction was normalized by insulin treatment. Conclusions: The decreased renal NOS activity during the late phase of diabetes is partially associated with a decrease in neuronal NOS activity and protein expression in kidney macula densa.

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“…It is characterized by marked hyperphagia, reduced thermogenesis, and impaired secretion of most pituitary hormones (2). As the hypothalamus appears to be important in the regulation of food intake and energy balance, these energetic and neuroendocrine disturbances seen in diabetes may be mediated by changes in the levels and distributions of specific hypothalamic neurons and neurotransmitters (3).…”

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confidence: 99%

“…Numerous studies have shown that insulin deficiency-induced diabetes causes alteration in the activities of hypothalamic transmitters and neuropeptides (3,15); Serino et al (3) demonstrated that enhanced NOS gene expression takes place in the hypothalamus in rats with STZ-induced diabetes.…”

mentioning

confidence: 99%

Administration of Folium mori Extract Decreases Nitric Oxide Synthase Expression in the Hypothalamus of Streptozotocin-Induced Diabetic Rats

Jang

Kim

Shin

et al. 2002

Japanese Journal of Pharmacology

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ABSTRACT-Folium mori, the leaves of Morus alba L., has traditionally been used for the treatment of diabetic hyperglycemia. It has been shown to induce enhanced NOS expression in the hypothalamus of rats with streptozotocin (STZ)-induced diabetes. In the present study, the effect of Folium mori on the expression of nitric oxide synthase (NOS) in the hypothalamus of STZ-induced diabetic rats was investigated via nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry. Enhanced NAPDH-d expression was detected in the paraventricular nucleus, ventromedial hypothalamic nucleus, and lateral hypothalamic area of the hypothalamus in the STZ-induced diabetes group. Administration of the aqueous extract of Folium mori to rats with STZ-induced diabetes resulted in decreased NADPH-d positivity. These results suggest that Folium mori treatment is effective in curbing the desire for food under diabetic conditions via modulation of NO expression in the hypothalamus.

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Upregulation of hypothalamic nitric oxide synthase gene expression in streptozotocin-induced diabetic rats

Cited by 50 publications

References 33 publications

Neuronal and endothelial nitric oxide synthase expression in outer medulla of streptozotocin-induced diabetic rat kidney

Neuronal and endothelial nitric oxide synthase expression in outer medulla of streptozotocin-induced diabetic rat kidney

Role of Renal Nitric Oxide Synthase in Diabetic Kidney Disease during the Chronic Phase of Diabetes

Administration of Folium mori Extract Decreases Nitric Oxide Synthase Expression in the Hypothalamus of Streptozotocin-Induced Diabetic Rats

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