Thursday, September 21, 2023
9/21/2023
PROJECT SUMMARY/ABSTRACT Kidney stones (KS) are painful mineral deposits that affect 1 in 11 individuals in the United States. The economic burden from KS is over $5 billion dollars annually and is predicted to rise due to increasing prevalence. Approximately 80% of KS are comprised of calcium oxalate (CaOx). Several individuals with CaOx KS develop recurrent KS. The reasons for recurrence are not well defined. Intake of meals containing high amounts of oxalate are associated with increased KS risk. Oxalate-rich diets may induce CaOx crystal formation in the urine and nephron, which can stimulate reactive oxygen species signaling and monocyte recruitment into the renal interstitium. If crystals are not properly cleared by macrophages, this could result in the propagation of KS. Interleukin-10 (IL-10) is a key anti-inflammatory cytokine important for regulating monocyte and macrophage function. We previously reported patients with CaOx KS have reduced circulating monocyte cellular bioenergetics and increased inflammation. We further determined that CaOx crystals can cause similar responses in monocytes in vitro. We recently reported that intake of a single dietary oxalate load stimulates nanocrystalluria and alters circulating monocyte cellular bioenergetics in a small cohort of healthy subjects. The goals of this proposal are to examine the effects of low and high oxalate diets on nanocrystalluria and immunity using human translational studies and experimental models. The central hypothesis of this proposal is oxalate suppresses IL-10 signaling leading to reduced cellular bioenergetics, redox homeostasis, and mitochondrial quality control in macrophages. We further propose this contributes to impaired macrophage clearance of CaOx crystals from the kidney which may play a role in KS formation. Aim 1 will test the hypothesis that oxalate enriched diets stimulate nanocrystalluria and reduce monocyte cellular bioenergetics in healthy subjects and patients with CaOx KS. Aim 2 will test the hypothesis that oxalate reduces IL-10 signaling, cellular bioenergetics, and mitochondrial quality control in macrophages. This project involves an interdisciplinary team and multifaceted approaches to assess the effect of oxalate on nanocrystalluria and IL-10-mediated monocyte/macrophage immune responses, which may play a role in CaOx KS formation. The results obtained will generate new insights into the cellular mechanisms driving KS formation and should unveil novel strategies for KS prevention.
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