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

التفاصيل البيبلوغرافية
العنوان: Lipocalin 2 is essential for chronic kidney disease progression in mice and humans
المؤلفون: Bertrand Knebelmann, Gérard Friedlander, Tak W. Mak, Jonathan Barasch, Thorsten Berger, Clément Nguyen, Evangeline Pillebout, Kiyoshi Mori, Amandine Viau, Denise Laouari, Martine Burtin, Khalil El Karoui, Fabiola Terzi
المصدر: Journal of Clinical Investigation. 120:4065-4076
بيانات النشر: American Society for Clinical Investigation, 2010.
سنة النشر: 2010
مصطلحات موضوعية: Adult, Male, medicine.medical_specialty, Mice, Inbred Strains, Nephron, Biology, Lipocalin, urologic and male genital diseases, Cell Line, Lesion, Mice, Young Adult, Lipocalin-2, Downregulation and upregulation, Epidermal growth factor, Proto-Oncogene Proteins, Internal medicine, medicine, Polycystic kidney disease, Animals, Humans, Renal Insufficiency, Chronic, Aged, Mice, Knockout, Oncogene Proteins, Polycystic Kidney Diseases, Epidermal Growth Factor, Acute-phase protein, General Medicine, Middle Aged, Hypoxia-Inducible Factor 1, alpha Subunit, medicine.disease, Lipocalins, ErbB Receptors, medicine.anatomical_structure, Endocrinology, Disease Progression, Female, medicine.symptom, Acute-Phase Proteins, Research Article, Kidney disease
الوصف: 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.
تدمد: 0021-9738
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0cb596419bb714ec75a9ac6c20de964bTest
https://doi.org/10.1172/jci42004Test
حقوق: OPEN
رقم الانضمام: edsair.doi.dedup.....0cb596419bb714ec75a9ac6c20de964b
قاعدة البيانات: OpenAIRE