PGFC · Role of PPARgamma in the interstitial fluid volume regulation and contribution to cardiovascular complications of TZDs

Role of PPARgamma in the interstitial fluid volume regulation and contribution to cardiovascular complications of TZDs

We have carried out a cross-disciplinary research project (involving functional genetics, in vivo imaging, gene engineered animal models, renal and cardiovascular phenotyping) to facilitate the better understanding of renocardial effects of the thiazolidinedione (TZD)-type antidiabetic/antiatherogenic drugs and to find possible mechanisms to reduce their unwanted cardiovascular effects. TZDs are synthetic ligands of peroxisome proliferator activated receptor gamma (PPAR), which belongs to the heterodimer-forming nuclear receptor superfamily of ligand-dependent transcription factors. PPARforms a permissive heterodimer with retinoid X receptors (RXRs) and affects various cellular processes at the level of gene expression regulation. Additionally to its insulin sensitising effects, PPARregulates the expression of a range of inflammatory genes. This makes TZDs promising drugs in the treatment of inflammatory disorders, e. g. atherosclerosis, kidney disease and autoimmune inflammation. However, the immunomodulatory role of PPAR/RXRheterodimers is still undefined. As of medical importance, our studies show that activation of PPAR/RXRheterodimers in macrophages is a potential target in the resolution of autoimmune inflammation and the treatment of kidney disease. Moreover, activation of macrophage PPAR and RXRa potentially yields medical benefits in the treatment of autoimmunity. We have also shown that macrophage RXRa and RXR but not PPARcan affect the kidney-to-heart hormonal signaling (the renin-angiotensin aldosterone system) thereby establishing a link between inflammation, fluid retention and cardiac fibrosis. Our project also provides important data to the basic research. We have shown that PPARand RXRare essential for the proper expression of several cell surface receptors and complement molecules in macrophages, making PPAR/RXRheterodimer an important regulator of the phagocytosis. Our results also confirm that uptake of apoptotic cell debris increases anti-inflammatory macrophage phenotype acquisition by mitigating inflammatory gene transcription in a PPAR/RXR dependent manner. This mechanism can involve the interaction of PPAR/RXR with other transcription factors. Accordingly, macrophages deficient in PPARor RXRdisplay impaired phagocytosis and consequently reduced anti-inflammatory polarisation. Macrophage-specific deletion of PPARor RXRin mice leads to apoptotic cell accumulation in tissues, provoking autoimmune kidney disease. These results show that PPAR and RXR signaling in macrophages is essential for the efficient clearance of apoptotic cells and the maintenance of immunological self-tolerance, an important element of tissue homeostasis. Our studies also indicate that macrophage RXRs are involved in the progression of cardiac fibrosis in response to the activation of the renal blood pressure regulating hormonal cascade, the renin-angiotensin-aldosetrone system. Macrophage PPARand RXRs are therefore candidate targets for new medication strategies in the treatment of human autoimmune renal and cardiovascular disease and heart hypertrophy. Pharmacological targeting of RXRs may allow reduce the administration of TZDs in order to reach beneficial effects without cardiac complications. List of Keywords: PPAR???RXR, inflammation, autoimmunity, kidney, cardiovascular system, phagocytosis, nuclear receptors

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