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Published on: February 3, 2012
Lipocalin 2 is essential for chronic kidney disease progression in mice and humans
Amandine Viau1, Khalil El Karoui, Denise Laouari
1INSERM U845, Centre de Recherche Croissance et Signalisation, Université Paris Descartes, Hôpital Necker Enfants Malades, Paris, France.
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.
Insights
Chronic kidney disease (CKD) progression involves epidermal growth factor receptor (EGFR) and lipocalin 2 (Lcn2). Lcn2 drives CKD progression by mediating EGFR
Area of Science:
- Nephrology
- Molecular Biology
- Genetics
Background:
- Mechanisms driving chronic kidney disease (CKD) progression are not fully understood.
- Epidermal growth factor receptor (EGFR) is known to stimulate CKD progression, but its downstream molecular networks are unclear.
- Renal lesion severity varies among mouse strains after nephron reduction, requiring EGFR activation.
Purpose of the Study:
- To elucidate the molecular mechanisms of CKD progression.
- To identify the role of lipocalin 2 (Lcn2) in EGFR-mediated kidney damage.
- To investigate the relationship between EGFR, Lcn2, and hypoxia-inducible factor 1α (Hif-1α) in renal deterioration.
Main Methods:
- Utilized two mouse strains with differential responses to nephron reduction (FVB/N and B6D2F1).
- Performed genome-wide expression analysis to identify key genes.
- Investigated Lcn2 function using Lcn2 knockout mice (Lcn2-/-) and EGFR inhibition.
- Examined the role of Hif-1α in EGFR-induced Lcn2 overexpression.
Main Results:
- Lipocalin 2 (Lcn2) was the most highly upregulated gene in susceptible mice and actively promoted renal lesion progression.
- Lcn2 deficiency (Lcn2-/-) significantly reduced the severity of renal lesions.
- Lcn2 expression increased upon EGFR activation and mediated EGFR's mitogenic effects.
- EGFR inhibition prevented Lcn2 upregulation and lesion development.
- Hypoxia-inducible factor 1α (Hif-1α) was essential for EGFR-induced Lcn2 overexpression.
- Cell proliferation was markedly reduced in Lcn2-/- mice.
- Elevated LCN2 levels were observed in human CKD patients with rapid progression to end-stage renal failure.
Conclusions:
- Lipocalin 2 (Lcn2) is not merely a marker but an active mediator of EGFR-driven chronic kidney disease progression.
- A critical pathway involving EGFR, Hif-1α, and Lcn2 drives renal deterioration, cell proliferation, and cystogenesis.
- These findings offer novel insights into CKD pathogenesis and identify Lcn2 as a potential therapeutic target.
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