L-arginine pretreatment ameliorates Lipopolysaccharide-induced thyroid gland dysfunction in male albino rats

Bacterial infection is one of the most common causes of systemic inflammatory syndrome known as sepsis. Previous studies have been shown that sever sepsis was often complicated with secondary multiple organs dysfunction. This syndrome may greatly affect thyroid gland function leading to thyroid gland dysfunction. The objective of this study was to elucidate the effect of bacterial endotoxin (lipopolysaccharide, LPS) on thyroid gland function. The study extended to investigate the role of L-arginine (L-Arg) as immunomodulator in LPS-induced systemic inflammation. Eighty adults, male Wistar rats were randomly divided into four equal groups: The control group was intraperitoneally (IP) injected with physiological sterile saline (0.9% NaCl at dose 1 ml/kg body weight (BW)); LPS-treated group was injected with a single dose of LPS (1 mg/kg BW, IP); L-Argtreated group was injected with L-Arg (10 mg/kg BW, IP) once per day for 7 consecutive days; and L-Arg + LPS treated group was injected with L-Arg (10 mg/kg BW, IP) once per day for 7 consecutive days followed by a single dose of LPS (1 mg/kg BW, IP). Histopathological changes of thyroid gland, serum triiodothyronine (T3), thyroxine(T4), and thyroid stimulating hormone (TSH) levels were examined at 6, 12, 24 and 72 hours (h) after the last injection. Treatment of rats with a single dose of LPS alone resulted in thyroiditis which manifested by decreased serum T3 and T4 levels and severe necrosis of the thyroid follicles. However, in L-Arg-treated endotoxemic rats, pretreatment with L-Arg attenuated the LPS-induced acute thyroid gland injury

Regulation of CLC-Ka/barttin by the ubiquitin ligase Nedd4-2 and the serum- and glucocorticoid-dependent kinases

Regulation of ClC-Ka/barttin by the ubiquitin ligase Nedd4-2 and the serum- and glucocorticoid-dependent kinases.BackgroundClC-Ka and ClC-Kb, chloride channels participating in renal tubular Cl− transport, require the coexpression of barttin to become functional. Mutations of the barttin gene lead to the Bartter's syndrome variant BSND, characterized by congenital deafness and severe renal salt wasting. Barttin bears a proline-tyrosine motif, a target structure for the ubiquitin ligase Nedd4-2, which mediates the clearance of channel proteins from the cell membrane. Nedd4-2 is, in turn, a target of the serum- and glucocorticoid-inducible kinase SGK1, which phosphorylates and, thus, inactivates the ubiquitin ligase. ClC-Ka also possesses a SGK1 consensus site in its sequence. We hypothesized that ClC-Ka/barttin is stimulated by SGK1, and down-regulated by Nedd4-2, an effect that may be reversed by SGK1 and its isoforms, SGK2 or SGK3.MethodsTo test this hypothesis, ClC-Ka/barttin was heterologously expressed in Xenopus oocytes with or without the additional expression of Nedd4-2, SGK1, SGK2, SGK3, constitutively active S422DSGK1, or inactive K127NSGK1.ResultsExpression of ClC-Ka/barttin induced a slightly inwardly rectifying current that was significantly decreased upon coexpression of Nedd4-2, but not the catalytically inactive mutant C938SNedd4-2. The coexpression of S422DSGK1, SGK1, or SGK3, but not SGK2 or K127NSGK1 significantly stimulated the current. Moreover, S422DSGK1, SGK1, and SGK3 also phosphorylated Nedd4-2 and thereby inhibited Nedd4-2 binding to its target. The down-regulation of ClC-Ka/barttin by Nedd4-2 was abolished by elimination of the PY motif in barttin.ConclusionClC-Ka/barttin channels are regulated by SGK1 and SGK3, which may thus participate in the regulation of transport in kidney and inner ear