Abstract: PO2129
Macrophage Neutrophil Gelatinase-Associated Lipocalin Has a Critical Role in Aldosterone-Induced Renal Fibrosis via the CCL5-IL4 Pathway
Session Information
- Mechanisms of Kidney and Vascular Disease
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1403 Hypertension and CVD: Mechanisms
Authors
- Bonnard, Benjamin, INSERM U1138, PARIS, France
- Genty, Marie, INSERM U1138, PARIS, France
- Ibarrola, Jaime, Universidad Publica de Navarra, Pamplona, Navarra, Spain
- Fernández-Celis, Amaya, Universidad Publica de Navarra, Pamplona, Navarra, Spain
- Lopez-Andres, Natalia, Universidad Publica de Navarra, Pamplona, Navarra, Spain
- Jaisser, Frederic, INSERM U1138, PARIS, France
Background
Neutrophil Gelatinase-Associated Lipocalin (NGAL) (or lipocalin 2) is a novel mineralocorticoid biotarget in the cardiovascular system. NGAL is also described as an acute renal lesion biomarker and NGAL serum concentration is associated with the severity of renal damages patients with a chronic kidney disease (CKD). Lipocalin2 (Lcn2) gene invalidation in a CKD mouse model protects from proteinuria and renal lesions.
We hypothesized that NGAL produced from macrophages promotes expression of chemoattractant molecules involved in renal lesions induced by mineralocorticoid excess.
Methods
The role of Lcn2 was analyzed using full Lcn2 knock out mice (NGAL KO) challenged with uni-Nephrectomy, Aldosterone 200 mg/kg/day, Salt 1% (NAS model) during 6 weeks. Assessment of CCL5/IL4 in kidney fibrosis were studied using maraviroc administration (50 mg/kg/d in chow diet) or by injections of anti-IL4 antibody (600 mg/week).
Results
NAS induced a significant increase in the expression (relative values, mean±SEM, compared to 1 in the control samples, p<0.05) of extracellular matrix proteins such as collagen I (2.35±0.33), a-SMA (2.04±0.44) and fibronectin (3.38±0.42) in the kidney of WT mice associated with interstitial kidney fibrosis (6.49±0.70). This is fully prevented by Lcn2 deletion. Expression of macrophages markers F4/80, CD80 and CD86 was increased (5.11±0.46, 4.84±0.19 and 5.22±0.45 respectively) in WT NAS mice and partly prevented in Lcn2 KO mice. Macrophages isolated from Lcn2 KO or WT mice were co-treated with aldosterone (10-8M) and NaCl (40mM). In WT macrophages, expression of Lcn2 (2.81±0.30) and the CCL5 chemokine (2.48±0.32) was increased. The increase of CCL5 was blunted in Lcn2 KO macrophages. Similarly to Lcn2 inactivation, CCL5 receptor blockade improved renal fibrosis and reduced high levels of Th2 CD4+ cell markers induced by NAS. Neutralization of IL4, a Th2 cytokine, in NAS mice injected with anti-IL4 antibody blunted kidney fibrosis and overexpression of profibrotic proteins such as collagen I, a-SMA and fibronectin.
Conclusion
NGAL produced by macrophages plays a critical role in renal interstitial fibrosis through the CCL5/IL4 pathway in mice exposed to mineralocorticoid excess.