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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Suppression of Rapidly Progressive Mouse Glomerulonephritis with the Non-Steroidal Mineralocorticoid Receptor Antagonist BR-4628
Frank Y. Ma,Frank Y. Ma,Yingjie Han,Yingjie Han,David J. Nikolic-Paterson,David J. Nikolic-Paterson,Peter Kolkhof,Gregory H Tesch,Gregory H Tesch +8 more
TL;DR: The non-steroidal MRA (BR-4628) provided substantial suppression of mouse crescentic glomerulonephritis without causing tubular dysfunction, and warrants further investigation of non- Steroidal MRAs as a therapy for inflammatory kidney diseases.
Journal ArticleDOI
The role of the mineralocorticoid receptor in immune cells in cardiovascular disease
Jesse Jääsaari,07065086538 +1 more
TL;DR: In this article , the authors identify the mineralocorticoid receptor (MR) on immune cells as a potential target to modulate inflammation and identify the molecular targets for these non-renal actions of the MR.
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Nonepithelial mineralocorticoid receptor activation as a determinant of kidney disease.
TL;DR: The role of the mineralocorticoid receptor (MR) in the regulation of fluid and electrolyte homeostasis via differential gene expression, and its role in modulating inflammation and fibrosis has been identified as mentioned in this paper .
Journal ArticleDOI
Finerenone: a mineralocorticoid receptor antagonist for the treatment of chronic kidney disease associated with type 2 diabetes
Edgar V. Lerma,Daniel J. Wilson +1 more
TL;DR: Finerenone has demonstrated a favorable benefit-risk profile offering an effective new treatment for patients with CKD associated with T2D, and compares the properties of finerenone with those of the older steroidal MRAs spironolactone and eplerenone.
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Vascular and inflammatory mineralocorticoid receptors in kidney disease.
TL;DR: Data is reviewed showing the cellular consequences of MR activation in endothelial, smooth muscle and inflammatory cells and how this affects the kidney in pathological situations and the evidence demonstrating a benefit of pharmacological or genetic MR inhibition in various models of kidney disease is discussed.
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Mechanisms of Mineralocorticoid Action
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