warfarin and Hypertrophy

Nephropathy is one of the most common and severe complications of diabetes mellitus. The mechanism of diabetic nephropathy, however, remains incompletely understood. To elucidate the mechanism of diabetic nephropathy, we focus on the role of a vitamin K-dependent growth factor, growth arrest-specific gene 6 (Gas6), and its receptor Axl in the pathogenesis of diabetic nephropathy. We used streptozotocin (STZ)-induced diabetic rats and mice as a model of diabetic nephropathy and examined the role of Gas6 and Axl in the development of diabetic nephropathy. We also studied signaling mechanisms involved in mesangial hypertrophy characteristic of the early phase of diabetic nephropathy in vitro. After 12 weeks of STZ injection, the glomerular expression of Gas6 and Axl was increased along with the phosphorylation of Akt, p70 S6 kinase, and 4E-BP-1. Administration of warfarin, which inactivates Gas6, inhibited mesangial and glomerular hypertrophy and the increase in albuminuria in STZ-rats. Warfarin treatment also inhibited the phosphorylation of Akt, p70 S6 kinase, and 4E-BP-1. To demonstrate the specific role of Gas6, we showed that these findings were recapitulated in STZ-induced Gas6-knockout mice and confirmed the role of Gas6 in the development of diabetic nephropathy in vivo. In vitro stimulation of mesangial cells with Gas6 resulted in mesangial cell hypertrophy. Stimulation of the cells with 25 mmol/l of glucose increased the expression of Gas6/Axl and mesangial cell size compared with that with 5.6 mmol/l of glucose. LY294002 and rapamycin blocked Gas6-induced activation of the Akt/mTOR pathway and mesangial hypertrophy. Thus, we have found a novel mechanism of glomerular hypertrophy through the Gas6/Axl-mediated pathway in the development of diabetic nephropathy, where the Akt/mTOR pathway is a key signaling cascade in Gas6-mediated mesangial and glomerular hypertrophy. Inhibition of the Gas6/Axl pathway in diabetic patients might be beneficial to slow down the progression of diabetic nephropathy.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Gene Expression; Glomerular Mesangium; Humans; Hypertrophy; Intercellular Signaling Peptides and Proteins; Mice; Mice, Knockout; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Warfarin

A 55-year-old man presented with recurrent brain infarction which had increased multifocally mainly in the cerebral white matter over the course of one year. Antibodies associated with antiphospholipid syndrome (APS) were initially negative. The patient was admitted to our department because of the thickened meninges shown on gadolinium enhanced brain MRI, mimicking hypertrophic pachymeningitis. However, blood and cerebrospinal fluid analysis revealed no significant inflammatory changes. On histopathological examination of the biopsied meninges, the arachnoid membrane was thickened with fibrosis, and arachnoidal microvessels were enlarged without significant inflammatory changes. The dura mater was not thickened, and no inflammation or microvessel enlargement were revealed. Finally, serum IgG anticardiolipin antibody testing was positive twice at an interval of more than 12 weeks, confirming the diagnosis of APS. Since initiating antithrombotic therapy with warfarin, brain infarction has not recurred. Without inflammation in the arachnoid membrane, the congestion of blood flow caused by thrombosis of microvessels in the arachnoid membrane might have increased the thickness of the arachnoid membrane.

Topics: Anticoagulants; Antiphospholipid Syndrome; Arachnoid; Biomarkers; Cardiolipins; Cerebral Infarction; Humans; Hypertrophy; Immunoglobulin G; Magnetic Resonance Imaging; Male; Microvessels; Middle Aged; Recurrence; Thrombosis; Treatment Outcome; Warfarin

Topics: Aged; Anticoagulants; Budd-Chiari Syndrome; Female; Granuloma, Plasma Cell; Humans; Hypertrophy; Liver Diseases; Tomography, X-Ray Computed; Warfarin

Nephropathy is one of the most common complications of diabetes mellitus. Glomerular hypertrophy is a hallmark in the early phase of the nephropathy. The mechanism of glomerular hypertrophy, however, remains incompletely understood. We have reported that Gas6 (growth arrest-specific gene 6) and its receptor, Axl, play a key role in the development of glomerulonephritis. Here we show the important role of Gas6/Axl in the pathogenesis of diabetic glomerular hypertrophy. In streptozotocin (STZ)-induced diabetic rats, mesangial and glomerular hypertrophy and an increase in the glomerular filtration rate (GFR) and albuminuria were observed after 12 weeks of STZ injection. The glomerular expression of Gas6 and Axl was increased in those rats. Administration of warfarin inhibited mesangial and glomerular hypertrophy and the increase in GFR and albuminuria in STZ rats. Moreover, we found less mesangial hypertrophy in STZ-treated Gas6 knockout mice than control mice. In vitro we found that stimulation of mesangial cells with Gas6 resulted in mesangial cell hypertrophy. Thus we have found a novel mechanism of glomerular hypertrophy through the Gas6/Axl-mediated pathway in the development of diabetic nephropathy. Inhibition of the Gas6/Axl pathway in diabetic patients might be beneficial to slow down the progression of diabetic nephropathy.

Topics: Albuminuria; Animals; Axl Receptor Tyrosine Kinase; Blotting, Western; Diabetic Nephropathies; Disease Progression; Flow Cytometry; Glomerular Filtration Rate; Humans; Hypertrophy; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Kidney; Kidney Diseases; Leucine; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Oncogene Proteins; Proteins; Proto-Oncogene Proteins; Rats; Receptor Protein-Tyrosine Kinases; Recombinant Proteins; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Warfarin