Role of lipocalin-2 in dietary and aldosterone-induced renal damages

Abstract

Study objective Both high fat diet and aldosterone challenge can cause significant renal damage, either as a primary cause or as co-morbidities with other diseases (e.g. cardiovascular diseases and diabetes). Angiotensin-converting-enzyme inhibitor (ACEi) and mineralocorticoid receptor inhibitor (MRi; e.g. spinronolactone and eplerenone) are commonly used in these patients. However their mortality is still high and such treatments are not suitable for all patients. Thus, a new therapeutic approach is warranted for renal damages. Herein, we hypothesize that lipocalin-2 plays a detrimental role in both dietary and aldosterone-induced renal injuries, and thus could be a novel drug target for therapeutic development. Methods Wild-type (WT), lipocalin-2 knockout (LKO) and lipocalin-2 tissue specific knockout in adipose tissue (ADN-Cre) mice were subjected to eight weeks of high fat diet treatment or to nephrectomy followed by four weeks of aldosterone/nephrectomy/1% saline treatment (ANS). MRi (either spinronolactone or eplerenone) was administered in ANS-treated groups to compare its efficacy versus lipocalin-2 deficiency mice in terms of anti-hypertensive effect, renal damages and fibrosis, and small resistance artery stiffness and tone. Adipose tissue of all mice was also collected for further analysis. Results Compared to MRi-treated wildtype mice, LKO and ADN-Cre mice showed a better protection against ANS-induced renal damages, as evidenced by: (1) attenuation of tissue fibrosis, (2) decreased infiltration of macrophages, (3) reduced levels of molecular injury markers, such as kidney injury marker (KIM)-1, monocyte chemoattractant protein (MCP)-1, transforming growth factor (TFG)-β and collagen I. In addition, LKO and ADN-Cre mice treated with high fat diet showed significant protection from renal damages and reduced adipose tissue fibrosis when compared to controls. As regards small resistance artery stiffness and compliance, ADN-Cre mice were protected against ANS and high fat diet challenge. Conclusion Lipocalin-2 is involved in the development of the metabolic-renal syndrome. Targeting its expression and/or signalling pathways could be a novel therapeutic approach to combat these medical complications.