Effect of mycophenolic acid in experimental, nontransplant glomerular diseases: new mechanisms beyond immune cells.
Mycophenolic acid (MPA) was introduced into clinical practice as immunosuppressive drug therapy to prevent allograft rejection. Since then, its clinical application has widened. Our goal was to review the lessons learned from experimental nontransplant glomerular disease models on the mechanisms of MPA therapy. T and B lymphocytes are preferentially dependent on de novo purine synthesis. By inhibiting the rate-limiting enzyme of de novo purine synthesis, MPA depletes the pool of deoxyguanosine triphosphate (dGTP) and inhibits proliferation of these immune cells. Furthermore, MPA can also induce apoptosis of immune cells and is known to inhibit synthesis of fucose- and mannose-containing membrane glycoproteins altering the surface expression and binding ability of adhesion molecules. However, MPA exerts a direct effect also on nonimmune cells. Mesangial cells are partially dependent on de novo purine biosynthesis and are thus susceptible to MPA treatment. Additionally, MPA can inhibit apoptosis in podocytes and seems to be beneficial in preserving the expression of nephrin and podocin, and by attenuation of urokinase receptor expression leads to decreased foot-process effacement. In summary, our manuscript sheds light on the molecular mechanisms underlying the antiproteinuric effect of MPA. Overall, MPA is an excellent treatment option in many immunologic glomerulopathies because it possesses immunosuppressive properties, has a remarkable effect on nonimmune cells and counteracts the proliferation of mesangial cells, expansion of mesangial matrix, and foot-process effacement of podocytes combined with a low systemic toxicity.
Pediatric Nephrology, Children's and Adolescents' Hospital, University Hospital of Cologne, Kerpener Street 62, 50937, Cologne, Germany. agnes.hackl@uk-koeln.de.
Agnes
A
Hackl
Pediatric Nephrology, Children's and Adolescents' Hospital, University Hospital of Cologne, Kerpener Street 62, 50937, Cologne, Germany.
Rasmus
R
Ehren
Pediatric Nephrology, Children's and Adolescents' Hospital, University Hospital of Cologne, Kerpener Street 62, 50937, Cologne, Germany.
Lutz Thorsten
LT
Weber
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D050533:Glomerular Basement Membrane / Q000187:drug effects / Q000378:metabolism; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism; D050527:Mesangial Cells / Q000187:drug effects / Q000502:physiology; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D009173:Mycophenolic Acid / Q000627:therapeutic use*; D009404:Nephrotic Syndrome / Q000188:drug therapy; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism; D011687:Purines / Q000378:metabolism; D051381:Rats
D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D011687:Purines; C113267:nephrin; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid
Experimental; Mesangial cells; Mycophenolate mofetil; Nonimmune effect of mycophenolic acid; Nontransplant glomerular diseases; Podocytes