In search of early events in the development of chronic kidney disease: the emerging role for lipocalin-2/NGAL.

In the October 2010 issue of the Journal of Clinical Investigation, Viau et al. [1] provided primary evidence for lipocalin-2 ([Lcn2; also known as neutrophil gelatinaseassociated lipocalin [(NGAL)], 24p3 protein, α1-microglobulin-related protein, or uterocalin]) as a central effector of progressive renal tissue damage upon acute kidney injury. Their studies are based on two experimental mouse strains which differed profoundly in their responses to 75% nephrectomy: whereas FVB/N mice develop severe renal lesions resembling features of human chronic kidney disease (CKD), B6D2F1mice are protected from early deterioration and instead exhibit compensatory alterations only. Post-surgical microarray analyses of the remnant renal tissues unravelled Lcn2 as the most markedly up-regulated gene in the FVB/N mice when compared to the B6D2F1 strain. Moreover, renal expression levels and urinary excretion of Lcn2 highly reflected the degree of tubular damage in the FVB/N mice, quite similar to humans with various forms of chronic kidney disease (CKD). Introduction of a homozygous disruption of the Lcn2 gene (i) largely abolished tubular cell proliferation, (ii) prevented the development of chronic renal lesions and (iii) preserved kidney function in FVB/N mice. The authors also identified Lcn2 as a downstreammediator following epidermal growth factor receptor (EGFR) activation. Genetically engineered mice with impaired EGF signalling did not up-regulate their Lcn2 levels and developed less severe renal damage in the remaining tissue after nephrectomy. Furthermore, EGFR activation mediated protein stabilization of the hypoxia-inducible factor (HIF)-1α, which accounted for increased Lcn2 expression.