Overview
Chronic kidney disease (CKD) is a public health threat affecting approximately 750 millions of people worldwide. Disordered bone and mineral metabolism is a nearly universal complication of CKD, collectively termed CKD-Mineral and Bone Disorder (CKD-MBD), that begins early and worsens progressively as kidney function declines. Elevated secretion of Fibroblast Growth Factor 23 (FGF23) from bone is among the earliest signs of disordered bone and mineral metabolism in CKD. High FGF23 levels are powerfully associated with greater risks of CKD progression, cardiovascular events, and mortality.
Recently, we and others have shown that inflammation and iron deficiency are potent stimuli of FGF23 production in human and animal studies. Both inflammation and iron deficiency are prevalent in the early stages of CKD, and contribute to mineral and bone alterations, including FGF23 excess, in CKD.
Our lab aims to establish the links between iron deficiency, inflammation and altered bone/mineral metabolism to capture novel regulatory loops affecting FGF23 regulation and function, in order to delay/prevent kidney disease progression and minimize adverse outcomes.
Phosphate, iron and FGF23
Elevated FGF23 maintains normal serum phosphate in CKD, but this compensation is ultimately maladaptive. FGF23 mediates an important component of CKD-related risk of death and FGF23 excess is associated with progression of chronic kidney disease, increased risk of mortality across all stages of CKD, in various CVD cohorts, and in the general population. As a possible pathophysiological link between elevated FGF23 and CKD progression and heart failure, we have shown that reduced iron and/or increased phosphate may contribute to FGF23 renal and cardiac toxicity. We have also shown that reducing dietary phosphate intake and increasing serum iron lowers FGF23 levels improves renal and cardiac function in mice with CKD, but to date the mechanisms at play remain poorly understood. Our ultimate goal is to establish a renal and cardiac molecular and physiological “imprint” for FGF23, iron and phosphate signaling in health and CKD.
Inflammation and FGF23
Despite recent advances in the field, the complex mechanisms that trigger elevations of FGF23 in CKD remain incompletely understood. Among these, we showed that inflammation contributes to FGF23 excess in mice with CKD and animals with intact kidney function. In CKD, there is a strong independent association between elevated levels of FGF23 and inflammatory markers, and we recently found that among the multiple pro-inflammatory cytokines, bone is the target of kidney-secreted lipocalin2(Lcn2 or human homologue NGAL) in CKD. In CKD, urine and serum LCN2 levels are elevated, in response to chronic kidney injury, inflammation and infiltrating cells. We further found that increased LCN2 stimulates bone production of FGF23 and contributes to cardiac disease in CKD.
HNF4α and osteogenesis
Renal osteodystrophy (ROD) is the bone disease associated with CKD. ROD is a disorder of bone cell function and metabolism leading to abnormal structure and compromised bone strength. The exact pathogenesis of ROD is poorly understood but it is often described as a particular subset of metabolic bone disease. We have recently discovered that hepatocyte nuclear factor 4 alpha (HNF4α), a highly conserved hepatic metabolic transcription factor, is also expressed in bone, in osteoblasts. We also found that HNF4α expression is nearly completely suppressed in bone from patients and mice with CKD, and that loss of HNF4α is strongly associated with bone disease in CKD.
Mir122
MicroRNA-based therapy can be promising due to its extreme efficiency in regulating distinct cell processes and its appealing property to target multiple targets. We found that miR-122 might be involved in the regulation of iron metabolism in CKD. Using animal models, functional genomics and pharmacological approaches, we will determine the source, specific targets and the molecular mechanisms involving miR-122 in anemia of CKD.
