Lipocalin-2: a novel link between the injured kidney and the bone

Abstract

Purpose of reviewFibroblast growth factor 23 (FGF23) excess is associated with left ventricular hypertrophy (LVH) and early mortality in patients with chronic kidney disease (CKD) and in animal models. Elevated Lipocalin-2 (LCN2), produced by the injured kidneys, contributes to CKD progression and might aggravate cardiovascular outcomes. The current review aims to highlight the role of LCN2 in CKD, particularly its interactions with FGF23. Recent findingsInflammation, disordered iron homeostasis and altered metabolic activity are common complications of CKD, and are associated with elevated levels of kidney-produced LCN2 and bone-secreted FGF23. A recent study shows that elevated LCN2 increases FGF23 production, and contributes to cardiac injury in patients and animals with CKD, whereas LCN2 reduction in mice with CKD reduces FGF23, improves cardiovascular outcomes and prolongs lifespan.

LCN2 and ELANE overexpression induces sepsis

“…[ 27 ] Lipocalin-2 is a biomarker for kidney injury and can be used for the early diagnosis of chronic kidney disease, contrast-induced nephropathy, and kidney transplantation. [ 28 ] LCN2 is a natural immune protein associated with acute and chronic inflammation, participating in the inflammatory state related to the current obesity epidemic. [ 29 ] In sepsis of intestinal origin, LCN2 reduces intestinal barrier damage by maintaining the dynamic balance of the microbiota, employing antioxidant strategies, and attenuating systemic inflammation by inactivating macrophages and inducing immune cell apoptosis.…”

Lipocalin-2 is associated with FGF23 in WNT1 and PLS3 osteoporosis

“…The direct stimulation of FGF23 production in bone by lipocalin-2 is at least partly mediated by activation of cAMP signaling in bone cells. The excess lipocalin-2 in kidney disease increases bone production of FGF23 and serum FGF23 levels, which contributes to the progression of the disorder ( 24 ). Decreasing FGF23 levels by inhibition of lipocalin-2 has been suggested as a therapeutic approach to improve outcomes in chronic kidney disease ( 23 ).…”

Fibroblast growth factor 23 is pumping iron: C-terminal-fibroblast growth factor 23 cleaved peptide and its function in iron metabolism

“…We previously called 'mineralostat' the process of sensing and regulating minerals, to maintain homeostasis or return to homeostasis following stress [54]. This mineralostat is highly relevant and of paramount interest in medical research because it contains the elusive mechanism that fails in chronic diseases such as CKD leading to profound alterations in mineral metabolism and eventually skeletal abnormalities [54,55].…”

“…We previously called 'mineralostat' the process of sensing and regulating minerals, to maintain homeostasis or return to homeostasis following stress [54]. This mineralostat is highly relevant and of paramount interest in medical research because it contains the elusive mechanism that fails in chronic diseases such as CKD leading to profound alterations in mineral metabolism and eventually skeletal abnormalities [54,55]. Thus, iron metabolism could be part of the 'mineralostat' designation of the mechanisms leading to increased FGF23 production and opens a number of questions to understand how and why phosphate loading and iron deficiency would both regulate the same hormone, if in turn this hormone regulates only phosphate excretion and vitamin D metabolism [56][57][58].…”