Myeloid Mineralocorticoid Receptor Activation Contributes to Progressive Kidney Disease
Louis Huang,David J. Nikolic-Paterson,Yingjie Han,Elyce Ozols,Frank Y. Ma,Morag J. Young,Greg H. Tesch +6 more
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TLDR
Myeloid deficiency of MR provides protection similar to eplerenone in this disease, and MR signaling in myeloid cells, but not podocytes, contributes to the progression of renal injury in mouse GN.Abstract:
Clinical and experimental studies have shown that mineralocorticoid receptor (MR) antagonists substantially reduce kidney injury. However, the specific cellular targets and mechanisms by which MR antagonists protect against kidney injury must be identified. We used conditional gene deletion of MR signaling in myeloid cells (MR flox/flox LysM Cre mice; MyMRKO) or podocytes (MR flox/flox Pod Cre mice; PodMRKO) to establish the role of MR in these cell types in the development of mouse GN. Accelerated anti–glomerular basement membrane GN was examined in groups of mice: MyMRKO, PodMRKO, wild-type (WT) littermates, and WT mice receiving eplerenone (100 mg/kg twice a day; EPL-treated). At day 15 of disease, WT mice had glomerular crescents (37%±5%), severe proteinuria, and a 6-fold increase in serum cystatin-C. MyMRKO, PodMRKO, and EPL-treated mice with GN displayed proteinuria similar to that in these disease controls. However, MyMRKO and EPL-treated groups had a 35% reduction in serum cystatin-C levels and reduced crescent numbers compared with WT mice, whereas PodMRKO mice were not protected. The protection observed in MyMRKO mice appeared to result predominantly from reduced recruitment of macrophages and neutrophils into the inflamed kidney. Suppression of kidney leukocyte accumulation in MyMRKO mice correlated with reductions in gene expression of proinflammatory molecules (TNF- α , inducible nitric oxide synthase, chemokine (C-C motif) ligand 2, matrix metalloproteinase - 12), tubular damage, and renal fibrosis and was similar in EPL-treated mice. In conclusion, MR signaling in myeloid cells, but not podocytes, contributes to the progression of renal injury in mouse GN, and myeloid deficiency of MR provides protection similar to eplerenone in this disease.read more
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Macrophages: versatile players in renal inflammation and fibrosis
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Steroidal and Novel Non-steroidal Mineralocorticoid Receptor Antagonists in Heart Failure and Cardiorenal Diseases: Comparison at Bench and Bedside
Peter Kolkhof,Frederic Jaisser,So Young Kim,Gerasimos Filippatos,Christina Nowack,Bertram Pitt +5 more
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Journal Article
The selective mineralocorticoid receptor antagonist eplerenone is protective in mild anti-GBM glomeru-lonephritis
Emanuel Zitt,Kathrin Eller,Julia M. Huber,Alexander H. Kirsch,Andrea Tagwerker,Gert Mayer,Alexander R. Rosenkranz +6 more
TL;DR: In this paper, the selective aldosterone-receptor antagonist eplerenone has a profound anti-inflammatory effect in the autologous phase of anti-glomerular basement membrane (GBM) glomerulonephritis (GN).
Journal ArticleDOI
Aldosterone mediates glomerular inflammation in experimental mesangial proliferative glomerulonephritis
TL;DR: MRA alters glomerular inflammation and mesangial cell activation in experimentalglomerular injury and may be a novel way to treat acute glomerulonephritis.
Original Article The selective mineralocorticoid receptor antagonist eplerenone is protective in mild anti-GBM glomeru- lonephritis
Emanuel Zitt,Kathrin Eller,Julia M. Huber,Alexander H. Kirsch,Andrea Tagwerker,Gert Mayer,Alexander R. Rosenkranz +6 more
TL;DR: Aldosterone-receptor blockade by eplerenone effectively attenuated proteinuria, kidney damage and the inflammatory response in anti-GBM GN by significantly decreasing pro-inflammatory cytokines in the regional draining lymph nodes of the kidney.
Journal ArticleDOI
LF15-0195 prevents the induction and inhibits the progression of rat anti-GBM disease.
Greg H. Tesch,Prudence A. Hill,Mu Wei,David J. Nikolic-Paterson,Patrick Dutartre,Robert C. Atkins +5 more
TL;DR: LF15-0195 prevents the induction and suppresses the progression of rat anti-GBM disease through multiple mechanisms of action, suggesting that this drug may have significant therapeutic potential in human glomerulonephritis.