Identification of Ceruloplasmin as a Gene that Affects Susceptibility to Glomerulonephritis Through Macrophage Function

Abstract

Crescentic glomerulonephritis (Crgn) is a complex disorder where macrophage activity and infiltration are significant effector causes. In previous linkage studies using the uniquely susceptible Wistar Kyoto (WKY) rat strain, we have identified multiple crescentic glomerulonephritis QTL (Crgn) and positionally cloned genes underlying Crgn1 and Crgn2, which accounted for 40% of total variance in glomerular inflammation. Here, we have generated a backcross (BC) population (n = 166) where Crgn1 and Crgn2 were genetically fixed and found significant linkage to glomerular crescents on chromosome 2 (Crgn8, LOD = 3.8). Fine mapping analysis by integration with genome-wide expression QTLs (eQTLs) from the same BC population identified ceruloplasmin (Cp) as a positional eQTL in macrophages but not in serum. Liquid chromatography-tandem mass spectrometry confirmed Cp as a protein QTL in rat macrophages. WKY macrophages overexpress Cp and its downregulation by RNA interference decreases markers of glomerular proinflammatory macrophage activation. Similarly, short incubation with Cp results in a strain-dependent macrophage polarization in the rat. These results suggest that genetically determined Cp levels can alter susceptibility to Crgn through macrophage function and propose a new role for Cp in early macrophage activation.

BCAT1 controls metabolic reprogramming in activated human macrophages and is associated with inflammatory diseases

“…Here, we demonstrate that Bcat1 is a druggable target for controlling inflammation in two distinct chronic inflammatory diseases characterized by antibody-mediated end-organ damage with macrophage infiltration. The rat model of crescentic glomerulonephritis in the WKY strain is dependent on macrophage infiltration and activation in response to glomerular deposition of immunoglobulin 21 59 60 . Primary macrophages from the WKY strain show a genetically determined Hif-1α-mediated glycolytic transcriptome signature during their differentiation 61 , suggesting a genetically determined metabolic state that could explain their unique susceptibility to glomerular inflammation.…”

COVID-19: The Potential Role of Copper and N-acetylcysteine (NAC) in a Combination of Candidate Antiviral Treatments Against SARS-CoV-2

“…Copper may also have a role in the immune system response to inflammation (67)(68)(69)(70)(71)(72)(73)(74). In inflammatory conditions, subjects exhibited higher mean serum copper concentrations related to disease activity (67,68).…”

“…In vitro studies have shown that ceruloplasmin may have a pathophysiological role in inflammatory diseases, acting as a physiologic inhibitor of myeloperoxidase (MPO) (72). Another study in a crescentic glomerulonephritis (Crgn) animal model showed the down-regulation of ceruloplasmin by RNA interference (RNAi), decreased markers of glomerular proinflammatory macrophage activation and suppressed a physiological response (73). Exogenous copper decreased the formation of systemic lupus erythematosus (SLE) cells in rats with a hydralazine induced collagen disease (74).…”

Deferiprone, an Iron Chelator, is Preventive and Therapeutic in Experimental Crescentic Glomerulonephritis

“…12,13 Superoxide anions are the precursor of most other ROS, 35 and their production by macrophages has been shown to be a prominent contributor to the glomerular injury in glomerulonephritis. 15,36,37 To test whether deferiprone protects cells from superoxide induced oxidative stress, we stimulated BMDMs with phorbol 12-myristate 13-acetate (PMA), which is a widely used superoxide inducer in innate immune cells such neutrophils and macrophages. 38,39 Deferiprone markedly decreased the superoxide anions detected in stimulated BMDMs ( Figure 3A).…”

“…This latter finding suggested that macrophage iron metabolism could contribute to the pathogenesis of crescentic glomerulonephritis. 15 Iron participates in many aspects of cellular biology and is essential for life as its deprivation leads to inactivation of ribonucleotide reductase (RNR), the enzyme essential for DNA synthesis. [16][17][18] Thus iron chelation emerges as an alternative anti-cancer and immunosuppressive therapy.…”