Cell volume regulatory mechanisms in progression of renal disease

One of the striking morphological features of renal failure is an increase of cell volume. This review explores the role of cell volume regulatory mechanisms in the pathophysiology of progressive renal disease. The case is made that TGF-beta, a major cytokine involved in the development of progressive renal failure, upregulates the transcription of the serum and glucocorticoid-dependent kinase hSGK1,involved in cell volume regulation. Excessive extracellular glucose concentrations stimulate TGF-beta1 expression and thus similarly enhance hSGK1-transcription. The kinase stimulates two mechanisms important for cell volume regulation, i.e. the renal epithelial Na+ channel ENaC and the thick ascending limb Na+,K+,2Cl(-) cotransporter BSC1. On the one hand, stimulation of renal tubular transport leads to renal retention of Na+, which favours the development of hypertension. On the other, the increase of cell volume stimulates protein synthesis and inhibits protein degradation, contributing to the enhanced net formation and deposition of matrix proteins. At later stages, the increase of cell volume may be reversed to atrophy, and cell death may lead to loss of functional tissue. In conclusion, progressive renal disease is paralleled by deranged cell volume regulatory mechanisms

Visual Deficit From Laser Interstitial Thermal Therapy for Temporal Lobe Epilepsy: Anatomical Considerations

Laser interstitial thermal therapy (LITT) is quickly emerging as an effective surgical therapy for temporal lobe epilepsy (TLE). One of the most frequent complications of the procedure is postoperative visual field cuts, but the physiopathology of these deficits is unknown. To evaluate potential causes of visual deficits after LITT for TLE in an attempt to minimize this complication. This retrospective chart review compares the case of a 24-year-old male who developed homonymous hemianopsia following LITT for TLE to 17 prior patients who underwent the procedure and suffered no visual deficit. We examined both features of the surgical approach (trajectory, laser energy, ablation size) and of preoperative surgical anatomy, derived from volumetric tracings of mesiotemporal structures. For the patient with postoperative homonymous hemianopsia imaging suggested inadvertent ablation of the lateral geniculate nucleus, although the laser was positioned entirely within the hippocampus. This patient's laser trajectory, ablation number, energy delivered, and ablation size were not significantly different from the prior patients. However, the subject with the visual deficit did have significantly smaller choroidal fissure cerebrospinal fluid volume. Visual deficits are the most common complication of LITT for mesiotemporal epilepsy and patients at most risk may have small cerebrospinal fluid volume in the choroidal fissure, allowing heat to spread from the hippocampal body to the lateral geniculate nucleus. When such anatomy is identified on preoperative magnetic resonance imaging, we recommend lowering laser trajectory, decreasing ablation power through the hippocampal body, and using temperature safety markers at the lower thalamic border

Serum- and glucocorticoid-dependent kinase, cell volume, and the regulation of epithelial transport

the regulation of cell volume. Given the limited selectivity of most inhibitors, however, the specific molecules involved have remained largely elusive. The search for cell volume regulated genes in liver HepG2 cells led to the discovery of the human serum- and glucocorticoid-dependent serine/threonine kinase hsgk1. Transcription and expression of hsgk1 is markedly and rapidly upregulated by osmotic and isotonic cell shrinkage. The effect of osmotic cell shrinkage on hsgk1 is mediated by p38 kinase. Further stimuli of hsgk1 transcription include glucocorticoids, aldosterone, TGF-β1, serum, increase of intracellular Ca2+ and phorbolesters, whereas cAMP downregulates hsgk1 transcription. The hsgk1 protein is expressed in several epithelial tissues including human pancreas, intestine, kidney, and shark rectal gland. Co-expression of hsgk1 with the renal epithelial Na+-channel ENaC or the Na+/K+/2Cl--cotransporter NKCC2 (BSC1) in Xenopus oocytes, accelerates insertion of the transport proteins into the cell membrane and thus, stimulates channel or transport activity. Thus, hsgk1 participates in the regulation of transport by steroids and secretagogues increasing intracellular Ca2+-activity. The stimulation of hsgk1 transcription by TGF-β1 may further bear pathophysiological relevance

Expression of the Serine/Threonine Kinase hSGK1 in Chronic Viral Hepatitis

The human serine/threonine kinase hSGK1 is expressed ubiquitously with highest transcript levels in pancreas and liver. This study has been performed to determine the hSGK1 distribution in normal liver and its putative role in fibrosing liver disease. HSGK1-localization was determined by in situ hybridization, regulation of hSGK1-transcription by Northern blotting, fibronectin synthesis and hSGK1 phosphorylation by Western blotting. In normal liver hSGK1 was mainly transcribed by Kupffer cells. In liver tissue from patients with chronic viral hepatitis, hSGK1 transcript levels were excessively high in numerous activated Kupffer cells and inflammatory cells localized within fibrous septum formations. HSGK1 transcripts were also detected in activated hepatic stellate cells. Accordingly, Western blotting revealed that tissue from fibrotic liver expresses excessive hSGK1 protein as compared to normal liver. TGF-β1 (2 ng/ml) increases hSGK1 transcription in both human U937 macrophages and HepG2 hepatoma cells. H2O2 (0.3 mM) activated hSGK1 and increased fibronectin formation in HepG2 cells overexpressing hSGK1 but not in HepG2 cells expressing the inactive mutant hSGK1K127R. In conclusion hSGK1 is upregulated by TGF-β1 during hepatitis and may contribute to enhanced matrix formation during fibrosing liver disease

Cerebral localization and regulation of the cell volume-sensitive serum- and glucocorticoid-dependent kinase SGK1

The serum- and glucocorticoid-dependent kinase SGK1 is regulated by alterations of cell volume, whereby cell shrinkage increases and cell swelling decreases the transcription, expression and activity of SGK1. The kinase is expressed in all human tissues studied including the brain. The present study was performed to localize the sites of SGK1 transcription in the brain, to elucidate the influence of the hydration status on SGK1 transcription and to explore the functional significance of altered SGK1 expression. Northern blot analysis of human brain showed SGK1 to be expressed in all cerebral structures examined: amygdala, caudate nucleus, corpus callosum, hippocampus, substantia nigra, subthalamic nucleus and thalamus. In situ hybridization and immunohistochemistry in the rat revealed increased expression of SGK1 in neurons of the hippocampal area CA3 after dehydration, compared with similar slices from brains of euvolaemic rats. Additionally, several oligodendrocytes, a few microglial cells, but no astrocytes, were positive for SGK1. The abundance of SGK1 mRNA in the temporal lobe, including hippocampus, was increased by dehydration and SGK1 transcription in neuroblastoma cells was stimulated by an increase of extracellular osmolarity. Co-expression studies in Xenopus laevis oocytes revealed that SGK1 markedly increased the activity of the neuronal K+ channel Kv1.3. As activation of K+ channels modifies excitation of neuronal cells, SGK1 may participate in the regulation of neuronal excitability

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

Transforming growth factor β (TGF-β) has been shown to participate in the pathophysiology of diabetic complications. As shown most recently, TGF-β stimulates the expression of a distinct serine/threonine kinase (hSGK) which had previously been cloned