Fibroblast growth factor (FGF) 23 is a phosphate regulating hormone normally produced by bone. In chronic kidney disease (CKD), accumulation of circulating bioactive intact FGF23 (iFGF23), due to increased Fgf23 transcription and decreased FGF23 de-activating cleavage, is independently associated with cardiovascular mortality. Novel therapeutic approaches to reduce FGF23 levels and prevent adverse outcomes in CKD are desperately needed but current therapies are suboptimal. Iron deficiency (ID) and inflammation are powerful stimuli of FGF23 transcription and cleavage. In healthy mice, FGF23 production is highly increased in response to ID and inflammation, but only mild increases in serum iFGF23 levels are observed due to concomitant increase in FGF23 cleavage. miR-122 increases FGF23 cleavage and is highly elevated in response to ID and inflammation. In CKD, we show that the expression of miR-122 is reduced despite ID and inflammation, FGF23 cleavage is impaired, and ID and inflammation therefore contribute to increased iFGF23 levels. We showed that partial correction of ID or inflammatory component in mice with CKD reduced FGF23 transcription, corrected FGF23 levels and prevented development of cardiac disease and premature death. However, bone-specific deletion of FGF23 was not sufficient to fully correct FGF23 levels in iron deficient or inflamed mice, suggesting that additional cell targets produce FGF23 in response to ID and inflammation. In fact, we show that erythroid cells and macrophages also contribute to FGF23 excess. In this innovative proposal, we will test the hypothesis that erythroid and macrophage cell lineage contribute to increased production of FGF23 in response to ID and inflammation, and that lower miR-122 result in impaired FGF23 cleavage in health and in CKD.
In Aim1, we will determine if FGF23 is produced by bone and macrophages in response to inflammation and by bone and erythroid cells in response to iron deficiency. We will use inflammatory challenges and dietary iron restriction in mice with cell lineage specific deletion of FGF23.
In Aim2, we will assess the role of miR-122 in response to ID and inflammation on FGF23 cleavage using genetic deletion of miR-122 and administration of miR-122 antagonists in mice.
In Aim 3, we will test the therapeutic potential of targeting the osteocytes, pre- osteoblasts, erythroid and macrophages in CKD, by using complementary genetic and pharmacological approaches to lower FGF23 in the Col4a3KO mouse model of CKD. We will also use genetic deletion of miR- 122 and administration of a miR-122 mimetic in mice with CKD to demonstrate the therapeutic potential of miR- 122 to increase FGF23 cleavage in CKD and prevent elevations of iFGF23 levels. We will measure FGF23 levels, and assess amelioration of kidney, bone and cardiac morphology and function. These innovative aims are supported by a productive collaborative team with expertise, skills and resources at Northwestern University that will further develop our understanding of FGF23 regulation, and support our ultimate goal of developing novel therapies to improve adverse outcomes in CKD.
Chronic Kidney Disease (CKD) is characterized by increased skeletal and extra-skeletal production of fibroblast growth factor (FGF)-23 that is associated with cardiovascular mortality. Inflammation, iron deficiency (ID) and reduced expression of miR-122 stimulate FGF23 production. This project proposes to test the impact of inflammation and ID on extra-skeletal sources of FGF23, and the role of miR-122 on the post-translational modifications of FGF23 in CKD, thus providing potential therapeutic targets for individuals with CKD.
| Neuburg, Samantha; Dussold, Corey; Gerber, Claire et al. (2018) Genetic background influences cardiac phenotype in murine chronic kidney disease. Nephrol Dial Transplant 33:1129-1137 |
| David, Valentin; Francis, Connor; Babitt, Jodie L (2017) Ironing out the cross talk between FGF23 and inflammation. Am J Physiol Renal Physiol 312:F1-F8 |
| Dev, Som; Babitt, Jodie L (2017) Overview of iron metabolism in health and disease. Hemodial Int 21 Suppl 1:S6-S20 |
| David, Valentin; Wolf, Myles (2016) Pruning the ricket thicket. J Clin Invest 126:473-6 |
| David, Valentin; Martin, Aline; Isakova, Tamara et al. (2016) Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int 89:135-46 |
| Francis, Connor; David, Valentin (2016) Inflammation regulates fibroblast growth factor 23 production. Curr Opin Nephrol Hypertens 25:325-32 |
