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
Citations
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Macrophages: versatile players in renal inflammation and fibrosis
TL;DR: The induction of MMT, via the Src-centric regulatory network mediated by transforming growth factor-β1 (TGFβ1)–Smad3, serves as a key checkpoint in the progression of chronic inflammation to renal fibrosis.
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F. Jaisser,N. Farman +1 more
TL;DR: Excess mineralocorticoid signaling now appears deleterious in the progression of pathologies that may lead to end-stage organ failure and could therefore benefit from the repositioning of pharmacological MR antagonists.
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Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine.
Rajiv Agarwal,Peter Kolkhof,George L. Bakris,Johann Bauersachs,Hermann Haller,Takashi Wada,Faiez Zannad +6 more
TL;DR: Overall, nonsteroidal MRAs appear to demonstrate a better benefit–risk ratio than steroidal MRAs, where risk is measured as the propensity for hyperkalaemia.
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Mineralocorticoid receptor antagonists and kidney diseases: pathophysiological basis
TL;DR: The available preclinical and clinical data support a benefit of using MRAs in CKD, an approach that should be further explored in future clinical trials.
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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
TL;DR: Novel, potent, and selective non-steroidal MRAs (third generation) were identified in drug discovery campaigns and a few entered clinical development recently, one of these is finerenone with different physicochemical, pharmacokinetics, and pharmacological properties in comparison with the steroidal MRAs.
References
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Mineralocorticoid Receptor Antagonist Reduces Renal Injury in Rodent Models of Types 1 and 2 Diabetes Mellitus
Christine Guo,Diego Martinez-Vasquez,Gonzalo P. Mendez,Maria F. Toniolo,Tham M. Yao,Eveline Oestreicher,Taisuke Kikuchi,Nathalie Lapointe,Luminita H. Pojoga,Gordon H. Williams,Vincent Ricchiuti,Gail K. Adler +11 more
TL;DR: Data suggest that MR activation is a critical factor in the early pathogenesis of renal disease in both type 1 and type 2 diabetes mellitus.
Journal ArticleDOI
Myeloid-Specific Deletion of the Mineralocorticoid Receptor Reduces Infarct Volume and Alters Inflammation During Cerebral Ischemia
Ryan A. Frieler,He Meng,Sheng-Zhong Duan,Stefan Berger,Günther Schütz,Yangdong He,Guohua Xi,Michael M. Wang,Michael M. Wang,Richard M. Mortensen +9 more
TL;DR: The data demonstrate that myeloid MR activation exacerbates stroke and identify myeloids MR as a critical target for MR antagonists, and indicate that MR activation has an important role in controlling immune cell function during the inflammatory response to stroke.
Journal ArticleDOI
Macrophage mineralocorticoid receptor signaling plays a key role in aldosterone-independent cardiac fibrosis
Laura A. Bienvenu,James P. Morgan,Amanda J. Rickard,Greg H. Tesch,Greg H. Tesch,Greg A. Cranston,Elizabeth K. Fletcher,Lea M.D. Delbridge,Morag J. Young,Morag J. Young +9 more
TL;DR: These data demonstrate that macrophage MR are necessary for the translation of inflammation and oxidative stress into interstitial and perivascular fibrosis after NO deficiency, even when plasma aldosterone levels are not elevated.
Journal ArticleDOI
Eplerenone Shows Renoprotective Effect by Reducing LOX-1–Mediated Adhesion Molecule, PKCε-MAPK-p90RSK, and Rho-Kinase Pathway
Naohiko Kobayashi,Kazuyoshi Hara,Akihiro Tojo,Maristela L. Onozato,Takeaki Honda,Kohtaro Yoshida,Shin-ichiro Mita,Shigefumi Nakano,Yusuke Tsubokou,Hiroaki Matsuoka +9 more
TL;DR: The results suggest that the renoprotective effects of eplerenone may be partly caused by inhibition of LOX-1–mediated adhesion molecules and PKC&egr;–MAP kinase–p90RSK pathway, and improvement in endothelial function.
Journal ArticleDOI
Mineralocorticoid receptor-associated hypertension and its organ damage: clinical relevance for resistant hypertension
Hirotaka Shibata,Hiroshi Itoh +1 more
TL;DR: In resistant hypertension, defined as a failure of concomitant use of three or more different classes of antihypertensive agents to control blood pressure, add-on therapy with mineralocorticoid receptor (MR) antagonists is frequently effective, which is designated as "MR-associated hypertension".