Lipocalin 2 is essential for chronic kidney disease progression in mice and humans

Abstract

Mechanisms of progression of chronic kidney disease (CKD), a major health care burden, are poorly understood. EGFR stimulates CKD progression, but the molecular networks that mediate its biological effects remain unknown. We recently showed that the severity of renal lesions after nephron reduction varied substantially among mouse strains and required activation of EGFR. Here, we utilized two mouse strains that react differently to nephron reduction -FVB/N mice, which develop severe renal lesions, and B6D2F1 mice, which are resistant to early deterioration -coupled with genome-wide expression to elucidate the molecular nature of CKD progression. Our results showed that lipocalin 2 (Lcn2, also known as neutrophil gelatinase-associated lipocalin [NGAL]), the most highly upregulated gene in the FVB/N strain, was not simply a marker of renal lesions, but an active player in disease progression. In fact, the severity of renal lesions was dramatically reduced in Lcn2 -/-mice. We discovered that Lcn2 expression increased upon EGFR activation and that Lcn2 mediated its mitogenic effect during renal deterioration. EGFR inhibition prevented Lcn2 upregulation and lesion development in mice expressing a dominant negative EGFR isoform, and hypoxia-inducible factor 1α (Hif-1α) was crucially required for EGFR-induced Lcn2 overexpression. Consistent with this, cell proliferation was dramatically reduced in Lcn2 -/-mice. These data are relevant to human CKD, as we found that LCN2 was increased particularly in patients who rapidly progressed to end-stage renal failure. Together our results uncover what we believe to be a novel function for Lcn2 and a critical pathway leading to progressive renal failure and cystogenesis.

Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia

“…Biomarkers of acute and chronic kidney injury, Havcr1 (KIM-1) and Lcn2 (neutrophil gelatinase-associated lipocalin), were up-regulated in the Mut −/− ;Tg INS-Alb-Mut kidneys. Lcn2, originally identified as a 25-kDa protein associated with neutrophil gelatinase (26), is largely produced by the tubular epithelium of the distal nephron after cellular damage and is associated with acute kidney injury (15), as well as chronic kidney disease progression (27). The murine and patient studies presented here demonstrate a strong correlation of Lcn2 with markers of oxidative stress.…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Boosting survival and regeneration of TECs might be renoprotective and antifibrotic as, for example, suggested for CSF-1 (143). Other TECs factors driving fibrosis include Notch (144), lipocalin-2 (NGAL) (28), kidney injury molecule-1 (KIM-1) (145), b-catenin signaling (146), and the EGFR (147,148). Paracrine signaling from damaged TECs is probably one of a major mechanisms driving renal fibrosis ( Figure 3).…”

“…Depending on the extent, duration and therapeutic manipulation, such inflammation might have various possible outcomes, from complete restitution to progressive kidney injury (28). The situation is somewhat different in transplant patients where inflammation is often associated with rejection, and the effects of non-rejection-associated inflammation are hard to dissect.…”

“…Different leukocyte subsets contribute to renal fibrosis in native kidneys (23,(28)(29)(30), in particular professional phagocytic and antigen-presenting cells, such as renal resident and infiltrating macrophages and dendritic cells. These cells exhibit a remarkable phenotypic plasticity and functional overlap.…”

“…They exert various functions depending on their phenotype and pathological context which can result in proor anti-fibrotic effects or have no effects at all (23,(31)(32)(33)(34)(35)(36)(37)(38)(39)(40). Apart from a number of chemokines driving their influx and activation such as CX3CR1 (28,30,31,41), several molecules also play an important role including galectin-3 (42,43), the receptor for macrophage colony-stimulating factor (44), the Wnt pathway ligand Wnt7b (45) and interleukin 10 (46).…”