Role of the SLC26A6 transporter in the clearance of oxalate crystals by macrophages

• Applicant: Professor Dr. Felix Knauf
• Subject Area: Nephrology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 515514134

Crystal-induced kidney disease refers to renal injury caused by intratubular crystal deposition. Oxalate nephropathy is characterized by kidney injury associated with crystals of calcium-oxalate in the renal parenchyma. During the last ten years it has been demonstrated that macrophages and dendritic cells play a critical role in crystal-induced kidney failure. Macrophages and dendritic cells surround oxalate crystals, activate the innate immune system and promote kidney inflammation, fibrosis, and organ failure. SLC26A6 is an oxalate transporter expressed in renal tubular and intestinal epithelial cells, where it mediates the secretion of oxalate into the urine and intestinal tract. Preliminary studies show that the SLC26A6 transporter is also expressed in human and murine immune cells, such as macrophages and dendritic cells. Moreover, our in vitro studies show that the SLC26A6 transporter is functional and seems to be the main oxalate transporter in macrophages. Interestingly, primary macrophages from Slc26a6-/- mice present higher intracellular levels of oxalate following exposure to oxalate when compared with macrophages from wild-type mice. This suggests that the transporter prevents oxalate overload in immune cells. Additionally, different groups of investigators have shown that macrophages participate in the phagocytosis of oxalate crystals both in vitro and in vivo, and soluble oxalate is released from macrophages in the process of oxalate crystal dissolution. However, the mechanism(s) that mediate the process of oxalate crystal dissolution and release from macrophages remain elusive. We hypothesize that SLC26A6 participates in the clearance of crystals by macrophages in oxalate-induced nephropathy. This is an important research question to examine as the deposition of oxalate crystals in the kidney is one of the initial processes that triggers oxalate nephropathy, an entity that lacks specific treatments. Therefore, knowing the mechanisms that participate in the phagocytosis and dissolution of oxalate crystals is of vital relevance to find new therapeutic targets. Hence, we aim to characterize the process of oxalate crystals clearance by macrophages focusing on the participation of the SLC26A6 transporter. To this end, we will compare the mechanism of crystal internalization, dissolution and subsequent secretion of soluble oxalate between wild-type and Slc26a6-/- primary macrophages to define the role of the transporter in the process. Importantly, we will address the role of the transporter in vivo during oxalate crystal clearance using a model of chronic oxalate nephropathy in wild-type mice and mice with oxalate transporter deficiency specifically in the cells of the immune system.

• DFG Programme: Research Grants