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      Enhanced Expression of Serum and Glucocorticoid-Inducible Kinase-1 in Kidneys of L-NAME-Treated Rats

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          Objective: The serum and glucocorticoid-inducible kinase-1 (SGK1) has previously been shown to be highly expressed in renal injury such as glomerulonephritis and diabetic nephropathy. Inhibition of nitric oxide synthase with N<sup>G</sup>-nitro- L-arginine methyl ester ( L-NAME) leads to arterial hypertension with subsequent renal injury. The present study explored whether chronic treatment with L-NAME affected renal SGK1 expression. Methods: 36 Sprague-Dawley rats were divided into a control group and an experimental group, in which hypertension was induced by oral administration of L-NAME (100 mg/kg/day). The rats were sacrificed 4 and 8 weeks, respectively, after initiation of the treatment. Blood pressure was determined with the tail-cuff method, urinary albumin and β<sub>2</sub>-microglobulin concentration were measured using an immunoturbidimetric assay, and SGK1 expression in renal cortex was quantified by real-time PCR and Western blotting. Results: The administration of L-NAME increased systolic blood pressure significantly from 107 to 135 mm Hg within 4 weeks and to 155 mm Hg within 8 weeks. It further enhanced urinary excretion of albumin and β<sub>2</sub>-microglobulin. Histology revealed marked fibrosis of glomerular and tubular tissue. The 4- and 8-week L-NAME treatment increased significantly (p < 0.01) SGK1 mRNA and protein abundance in renal cortex. Conclusions: L-NAME treatment leads to hypertension, proteinuria and renal fibrosis. It increases renal transcription and expression of SGK1, which has previously been shown to foster matrix protein deposition and could thus contribute to renal injury.

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          Most cited references 23

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          Deranged transcriptional regulation of cell-volume-sensitive kinase hSGK in diabetic nephropathy.

          Transforming growth factor beta (TGF-beta) has been shown to participate in the pathophysiology of diabetic complications. As shown most recently, TGF-beta stimulates the expression of a distinct serine/threonine kinase (hSGK) which had previously been cloned as an early gene transcriptionally regulated by cell volume alterations. The present study was performed to elucidate transcription and function of hSGK in diabetic nephropathy. As shown by Northern blotting, an increase of extracellular glucose concentration increased hSGK mRNA levels in cultured cells, an effect qualitatively mimicked by osmotic cell shrinkage or treatment with TGF-beta (2 microgram/liter), phorbol 12,13-didecanoate (1 microM), or the Ca(2+) ionophore ionomycin (1 microM) and blunted by high concentrations of nifedipine (10 and 100 microM). In situ hybridization revealed that hSGK transcription was markedly enhanced in diabetic nephropathy, with particularly high expression in mesangial cells, interstitial cells, and cells in thick ascending limbs of Henle's loop and distal tubules. According to voltage clamp and tracer flux studies in Xenopus oocytes expressing the renal epithelial Na(+) channel ENaC or the mouse thick ascending limb Na(+),K(+),2Cl(-) cotransporter BSC-1, coexpression with hSGK stimulated ENaC and BSC-1 11-fold and 6-fold, respectively, effects reversed by kinase inhibitors staurosporine (1 microM) and chelerythrine (1 microM) and not elicited by inactive hSGK. In conclusion, excessive extracellular glucose concentrations enhance hSGK transcription, which in turn stimulates renal tubular Na(+) transport. These observations disclose an additional element in the pathophysiology of diabetic nephropathy.
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            Effect of sodium intake on blood pressure and albuminuria in Type 2 diabetic patients: the role of insulin resistance.

             G. Lepore,  E Jori,  A. Tiengo (2004)
            This study was done to measure the effect of Na+ intake on blood pressure and albuminuria, in relation with insulin sensitivity and kidney haemodynamics, in Type 2 diabetic patients with and without microalbuminuria. Type 2 diabetic patients, 20 with microalbuminuria, 21 without, spent two consecutive 7-day periods, one on a high (250 mmol), the other on a low-Na+ (20 mmol) diet. Body weight, 24-h blood pressure and albuminuria were measured at the end of each period. At the end of high-Na+ diet insulin sensitivity (euglycaemic insulin clamp; 2 and kidney haemodynamics were measured in nine patients from each group. Switching from low to high-Na+ diet resulted in an increase in blood pressure (7.4+/-4.7 mmHg; p<0.001), body weight (1.9+/-0.4 kg; p<0.05) and albuminuria [from 80 (31-183) microg/min to 101 (27-965) microg/min; p<0.01) in patients with microalbuminuria. No changes occurred in patients without microalbuminuria. Patients with microalbuminuria also had greater intraglomerular pressure (44+/-1 mmHg vs 36+/-1; p<0.001), calculated from glomerular filtration rate, renal plasma flow, plasma protein concentration and the relationship between pressure and natriuresis. In these patients insulin sensitivity was lower (5.16+/-49 vs 7.36+/-0.63; p=0.007). Urinary albumin excretion (r=0.40; p=0.009) and insulin sensitivity (r=-0.59; p=0.01) were correlated with intraglomerular pressure. High salt intake increases blood pressure and albuminuria in Type 2 diabetic patients with microalbuminuria. These responses are associated with insulin resistance and increased glomerular pressure. Insulin resistance could contribute to greater salt sensitivity, increased glomerular pressure and albuminuria.
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              Stimulus-Dependent Regulation of Serum and Glucocorticoid Inducible Protein Kinase (SGK) Transcription, Subcellular Localization and Enzymatic Activity


                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                August 2006
                15 August 2006
                : 29
                : 2
                : 94-99
                a5th Medical Clinic, Faculty of Clinical Medicine, University of Heidelberg, Mannheim, and bDepartment of Physiology, University of Tübingen, Tübingen, Germany; cDepartment of Nephrology,Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
                93461 Kidney Blood Press Res 2006;29:94–99
                © 2006 S. Karger AG, Basel

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                Page count
                Figures: 3, Tables: 1, References: 27, Pages: 6
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                Original Paper

                Cardiovascular Medicine, Nephrology

                Fibrosis, NO synthase, Hypertension


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