Mechanistic Studies of a Novel Mycophenolic Acid-Glucosamine Conjugate That Attenuates Renal Ischemia/Reperfusion Injury in Rat

Renal ischemia/reperfusion (I/R) injury causes high mortality and morbidity during renal procedures, yet current drugs should be used at high doses or for long periods due to lack of tissue specificity. In previous work we described a novel mycophenolic acid glucosamine conjugate (MGC) that targets the proximal tubule epithelium, where it efficiently reduces renal I/R injury in rats and promotes recovery from reperfusion. Here we perform mechanistic studies of MGC in rats that suggest that the conjugate works by repressing the activation of renal inosine-5'-monophosphate dehydrogenase 2 (IMPDH2), thereby inhibiting the proliferation and accumulation of lympholeukocytes in the proximal tubules. In addition, MGC appears to inhibit inflammation through various pathways, including inhibition of free oxygen radical production, upregulation of bone morphogenetic protein-7, and downregulation of complement protein 3, TLR 4, intracellular adhesion molecules in the endothelium, proinflammatory cytokines (e.g., TNF-alpha, IL-6, IL-1, TGF-beta), and chemotactic cytokines [e.g., monocyte chemoattractant protein-1 (MCP-1) and IL-8]. These findings suggest that MGC specifically targets the proximal tubules and acts through numerous mechanisms to substantially mitigate I/R injury in rats; this conjugate may provide a more effective alternative to current combination therapy.