Antifibrotic effect of novel neutrophil gelatinase-associated lipocalin inhibitors in cardiac and renal disease models

Abstract

Neutrophil gelatinase-associated lipocalin (NGAL) is involved in cardiovascular and renal diseases. Gene inactivation of NGAL blunts the pathophysiological consequences of cardiovascular and renal damage. We aimed to design chemical NGAL inhibitors and investigate its effects in experimental models of myocardial infarction (MI) and chronic kidney disease induced by 5/6 nephrectomy (CKD) on respectively 8–12 weeks old C57Bl6/j and FVB/N male mice. Among the 32 NGAL inhibitors tested, GPZ614741 and GPZ058225 fully blocked NGAL-induced inflammatory and profibrotic markers in human cardiac fibroblasts and primary mouse kidney fibroblasts. The administration of GPZ614741 (100 mg/kg/day) for three months, was able to improve cardiac function in MI mice and reduced myocardial fibrosis and inflammation. The administration of GPZ614741 (100 mg/kg/day) for two months resulting to no renal function improvement but prevented the increase in blood pressure, renal tubulointerstitial fibrosis and profibrotic marker expression in CKD mice. In conclusion, we have identified new compounds with potent inhibitory activity on NGAL-profibrotic and pro-inflammatory effects. GPZ614741 prevented interstitial fibrosis and dysfunction associated with MI, as well as tubulointerstitial fibrosis in a CKD model. These inhibitors could be used for other diseases that involve NGAL, such as cancer or metabolic diseases, creating new therapeutic options.

Neutrophil Gelatinase-Associated Lipocalin From Macrophages Plays a Critical Role in Renal Fibrosis Via the CCL5 (Chemokine Ligand 5)-Th2 Cells-IL4 (Interleukin 4) Pathway

“…Recently, we described an antifibrotic effect of a new NGAL inhibitor in cardiac and renal disease models. 75 In the present study, renal fibrosis induced by mineralocorticoid excess was not fully prevented by the specific depletion of NGAL in macrophages suggesting that others sources of NGAL could be involved in fibrosis development and this should be assessed in future studies.…”

NGAL as a Potential Target in Tumor Microenvironment

“…Interestingly, Bonnard and co-workers identified by virtual screening two chemical compounds able to disrupt NGAL-NGALR interaction. These inhibitors blocked NGAL-induced inflammation and fibrosis in murine models of myocardial infarction and chronic kidney disease [108]. Even if these compounds did not act as inhibitors of siderophores binding to NGAL, however, they reduced NGAL-mediated intracellular iron delivery somehow.…”

Approaches towards tissue‐selective pharmacology of the mineralocorticoid receptor

“…NGAL deletion in mice attenuated post-myocardial infarction remodeling of the left ventricle (Martinez-Martinez et al, 2017). Recently, the anti-fibrotic properties of two chemical NGAL inhibitors, GPZ614741 and GPZ058225, targeting putative protein-protein interaction sites of NGAL have been evaluated (Bonnard et al, 2021). Both compounds effectively blocked NGAL-induced expression of inflammatory and fibrotic marker genes in cultured cardiac fibroblasts (Bonnard et al, 2021).…”

“…Recently, the anti-fibrotic properties of two chemical NGAL inhibitors, GPZ614741 and GPZ058225, targeting putative protein-protein interaction sites of NGAL have been evaluated (Bonnard et al, 2021). Both compounds effectively blocked NGAL-induced expression of inflammatory and fibrotic marker genes in cultured cardiac fibroblasts (Bonnard et al, 2021). In mice, long-term treatment with GPZ614741 improved left ventricular fibrosis and diastolic function after experimental myocardial infarction and prevented tubular injury and renal fibrosis after subtotal nephrectomy (Bonnard et al, 2021).…”

“…Both compounds effectively blocked NGAL‐induced expression of inflammatory and fibrotic marker genes in cultured cardiac fibroblasts (Bonnard et al, 2021). In mice, long‐term treatment with GPZ614741 improved left ventricular fibrosis and diastolic function after experimental myocardial infarction and prevented tubular injury and renal fibrosis after subtotal nephrectomy (Bonnard et al, 2021). Clinical data on NGAL inhibitors are not yet available.…”