Neutrophil Gelatinase-Associated Lipocalin from macrophages plays a critical role in renal fibrosis via the CCL5-Th2 cells-IL4 pathway.

Neutrophil gelatinase-associated lipocalin (NGAL) (or lipocalin 2, Lcn2) is a novel mineralocorticoid target in the cardiovascular system. Lcn2 gene invalidation protects against proteinuria and renal lesions in a chronic kidney disease mouse model. We hypothesized that NGAL produced from macrophages promotes the expression of chemoattractant molecules involved in renal lesions induced by mineralocorticoid excess.

The role of Lcn2 was analyzed using full (KO NGAL) or myeloid-specific (MF KO NGAL) Lcn2 knockout mice challenged with uni-nephrectomy, aldosterone, and salt (NAS) for six weeks. The role of the CCL5 and IL4 in kidney fibrosis was studied using maraviroc, a CCL5R antagonist, administration or by injections of an anti-IL4 neutralizing antibody.

NAS increased the renal expression of extracellular matrix proteins, such as collagen I, aSMA, and fibronectin, in WT mice, together with interstitial fibrosis. This was fully prevented in KO NGAL mice and partly prevented in MF KO NGAL mice. The expression of CCL5 was blunted in sorted macrophages from MF KO NGAL mice challenged by NAS and in macrophages obtained from KO NGAL mice and challenged ex vivo with aldosterone and salt. The pharmacological blockade of the CCL5 receptor improved renal fibrosis and reduced the high levels of Th2 CD4⁺ cells induced by NAS. Neutralization of IL4 in NAS mice blunted kidney fibrosis and the overexpression of profibrotic proteins, such as collagen I, aSMA, and fibronectin.

NGAL produced by macrophages plays a critical role in renal fibrosis through the CCL5/IL4 pathway in mice exposed to mineralocorticoid excess.