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
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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Finerenone: a New Mineralocorticoid Receptor Antagonist Without Hyperkalemia: an Opportunity in Patients with CKD?
TL;DR: Finererone holds promise for the future application of this new mineralocorticoid receptor antagonist class in patients with chronic kidney disease since it has shown a significant reduction in UACR combined with a safety profile similar to that in the placebo group, but further long-term studies investigating relevant clinical end points are warranted.
Journal ArticleDOI
Effect of a novel nonsteroidal selective mineralocorticoid receptor antagonist, esaxerenone (CS-3150), on blood pressure and renal injury in high salt-treated type 2 diabetic mice.
Abdus Sattar Bhuiyan,Abdus Sattar Bhuiyan,Abdus Sattar Bhuiyan,Kazi Rafiq,Kazi Rafiq,Kazi Rafiq,Hideki Kobara,Tsutomu Masaki,Daisuke Nakano,Akira Nishiyama +9 more
TL;DR: Data indicate for the first time that a nonsteroidal MR antagonist elicits renoprotective effects in diabetic kidney disease mice.
Journal ArticleDOI
miR-378 reduces mesangial hypertrophy and kidney tubular fibrosis via MAPK signalling
Bo Wang,Kevin Yao,Andrea F Wise,Ricky Wai Kiu Lau,Hsin-Hui Shen,Greg H. Tesch,Sharon D. Ricardo +6 more
TL;DR: The protective function of MAPK1 on miR-378 was shown in kidney cells treated with theMAPK1 inhibitor, selumetinib, which inhibited mesangial cell hypertrophy in response to TGF-β1.
Journal ArticleDOI
Nonsteroidal mineralocorticoid receptor antagonism for cardiovascular and renal disorders - New perspectives for combination therapy.
TL;DR: Major current clinical trials with MRAs in different CV and renal diseases are summarized and an outlook on further opportunities for combination therapy of nonsteroidal MRA finerenone with RAS inhibitors and sodium-glucose cotransporter-2 inhibitors is provided.
Journal ArticleDOI
Aldosterone and the Mineralocorticoid Receptor: Risk Factors for Cardiometabolic Disorders.
Rajesh Garg,Gail K. Adler +1 more
TL;DR: Preclinical studies have convincingly demonstrated a role for the mineralocorticoid receptor (MR) in adipose tissue physiology, and more data are needed to establish the benefits of MR antagonists in diabetes, obesity, and metabolic syndrome.
References
More filters
Journal ArticleDOI
A new method for large scale isolation of kidney glomeruli from mice.
Minoru Takemoto,Noomi Asker,Holger Gerhardt,Andrea Lundkvist,Bengt Johansson,Yasushi Saito,Christer Betsholtz +6 more
TL;DR: The method was applicable also to newborn mice, which allows for the isolation of immature developmental stage glomeruli and makes feasible transcript profiling and proteomic analysis of the developing, healthy and diseased mouse glomerulus.
Journal ArticleDOI
Myeloid mineralocorticoid receptor controls macrophage polarization and cardiovascular hypertrophy and remodeling in mice
Michael G. Usher,Sheng-Zhong Duan,Christine Y. Ivaschenko,Ryan A. Frieler,Stefan Berger,Günther Schütz,Carey N. Lumeng,Richard M. Mortensen +7 more
TL;DR: It is shown that myeloid MR is an important control point in macrophage polarization and that the function of MR on myeloids cells likely represents a conserved ancestral MR function that is integrated in a transcriptional network with PPARgamma and glucocorticoid receptor.
Journal ArticleDOI
Podocyte as the Target for Aldosterone: Roles of Oxidative Stress and Sgk1
TL;DR: In this article, the effects of aldosterone on podocyte, a key player of the glomerular filtration barrier, were investigated in uninephrectomized rats and fed a high-salt diet, where the podocyte injury was accompanied by renal reduced nicotinamide-adenine dinucleotide phosphate oxidase activation, increased oxidative stress, and enhanced expression of Sgk1.
Journal ArticleDOI
Podocyte-specific expression of cre recombinase in transgenic mice.
Marcus J. Moeller,Silja K. Sanden,Abdul Soofi,Roger C. Wiggins,Lawrence B. Holzman,Lawrence B. Holzman +5 more
TL;DR: A transgenic mouse line that expresses Cre recombinase exclusively in podocytes is reported, and Histological analysis of the kidneys showed that β‐gal expression was confined to podocytes.
Journal ArticleDOI
Mechanisms of Mineralocorticoid Action
Peter J. Fuller,Morag J. Young +1 more
TL;DR: A critical role for the MR in cardiovascular disease has now been demonstrated by the beneficial response to MR blockade in 2 large clinical trials in patients with cardiac failure, needed for the development of antagonists that target the cardiovascular system while avoiding the undesirable side effects of renal MR blockade.