1. Regulation of sphingolipid metabolism in cell culture and animal models of inflammatory kidney diseases.

A. Huwiler (group leader), A. Koch, I. Römer, S. Albert

In the last years, it has become clear that sphingolipids not only serve as inert structural components of cell membranes but may also exert important functions as signaling molecules under physiological and pathophysiological conditions. Especially ceramide and sphingosine 1-phosphate have attracted a lot of interest due to their potential involvement in regulation of the balance between cell death and survival, particularly with regard to tumor growth and therapy. However, the mechanisms that regulate the intracellular levels of these two sphingolipids are still poorly understood. Ceramide itself is connected with programmed cell death (apoptosis) in many cell types. It is generated by the action of sphingomyelinases of which several forms have been identified and that are activated by a variety of stress factors. According to their pH optimum they are divided into acid, neutral and alkaline subfamilies. To date, the relevant sphingomyelinase responsible for stress-induced ceramide accumulation is not yet identified. Once generated ceramide can activate several signaling cascades that ultimately lead to apoptosis. Alternatively, ceramide is degraded by ceramidases yielding sphingosine which serves as a substrate for the sphingosine kinase to form sphingosine-1-phosphate (S1P) which in turn is a potent mitogen for many cell types. As is the case for the sphingomyelinases the ceramidases are also divided into three subfamilies, the acid, neutral and alkaline form according to their pH optimum. Furthermore, two subtypes of the sphingosine kinase have been identified, the SK-1 and SK-2.
Particularly the neutral sphingomyelinase, the neutral ceramidase and the sphingosine kinases, which all are predominantly found in the cytosol or at the plasma membrane, are the most likely candidates for regulating the ceramide/S1P balance in the cell.
In one part of the project the neutral sphingomyelinase, the neutral ceramidase, and the sphingosine kinases are investigated including the regulation of their expressions and activities as well as their contributions to cell apoptosis and proliferation.
A second project focuses on the analysis and quantification of various sphingolipid species from cell extracts and tissues of healthy and diseased subjects by the method of tandem mass spectrometry (in collaboration with Prof. Geisslinger, Clinical Pharmacology).

2. Regulation of phospholipase A2 subtypes and their contribution to inflammatory processes in the kidney

A. Huwiler (group leader), S. Schwalm, S. Beyer

Phospholipase A2 (PLA2) constitutes a superfamily of enzymes that specifically release fatty acids, often arachidonic acid, from the sn-2 position of membrane phospholipids for production of important lipid mediators such as prostaglandins, leukotrienes or platelet-activating factor, which directly cause the cardinal symptoms of inflammation, i.e. redness, swelling, heat development or fever, pain and loss of function. High levels of secretory PLA2 have been found in serum and exudates from patients suffering from inflammatory diseases, like rheumatoid arthritis or acute pancreatitis and trauma. On the other side, the cPLA2 which was earlier proposed to be the responsible enzyme for physiological prostaglandin formation, is now more and more recognized as being inflammatory. Most convincing evidence araised from cPLA2 knockout mice which show significantly reduced acute lung injury, which is a characteristic feature of adult respiratory distress syndrome (ARDS) induced by sepsis syndrome. Furthermore, macrophages of cPLA2-deficent mice were unable to produce the inflammatory mediators PGE2 or LTB4 or LTC4. On the other hand, mice strains depleted of group IIA sPLA2, as is the widely used C57BL6 mice strain, do still develop inflammatory reactions.
Particularly in diseases such as rheumatoid arthritis, atherosclerosis or glomerulonephritis hypoxia is a prevalent factor that impacts the recruitment and function of immune cells and other aspects of disease progression.

One part of this project aims in investigating the effect of hypoxia on inflammatory parameters, particularly the expressions of the different PLA2s, cyclooxygenases and prostaglandin synthases, and the mechanisms involved.
Another part of the project focuses on the regulation of the cytosolic PLA2 and its contribution to prostaglandin formation under physiological and pathophysiological conditions.

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