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
Reads0
Chats0
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
More filters
Journal ArticleDOI
The myeloid mineralocorticoid receptor controls inflammatory and fibrotic responses after renal injury via macrophage interleukin-4 receptor signaling
Jonatan Barrera-Chimal,Jonatan Barrera-Chimal,Gabriel Rufino Estrela,Sebastian M. Lechner,Sébastien Giraud,Sébastien Giraud,Soumaya El Moghrabi,Shiem Kaaki,Peter Kolkhof,Thierry Hauet,Thierry Hauet,Frederic Jaisser,Frederic Jaisser +12 more
TL;DR: The studies support the rationale for using mineralocorticoid receptor antagonists in clinical practice to prevent transition of acute kidney injury to chronic kidney disease.
Journal ArticleDOI
The Role of the Mineralocorticoid Receptor in Inflammation: Focus on Kidney and Vasculature.
TL;DR: The mechanism for MR activation in tissue injury continues to evolve with the evidence to date suggesting that activation of MR results in a complex repertoire of effects involving both macrophages and T cells.
Journal ArticleDOI
Mineralocorticoid Receptor Signaling as a Therapeutic Target for Renal and Cardiac Fibrosis
Greg H. Tesch,Morag J. Young +1 more
TL;DR: In this review, recent insights into the profibrotic roles of MR signaling in kidney and cardiovascular disease are summarized and the potential benefits of novel non-steroidal MRAs for targeting kidney and cardiac fibrosis compared to existing steroidal MRAs are discussed.
Activation of local aldosterone system within podocytes is involved in apoptosis under diabetic conditions
Sun Ha Lee,Tae Hyun Yoo,Bo Young Nam,Dong Ki Kim,Jin Ji Li,Jin Ji Li,Dong Sub Jung,Seung Jae Kwak,Dong Ryeol Ryu,Seung Hyeok Han,Jung Eun Lee,Sung Jin Moon,Dae Suk Han,Shin Wook Kang +13 more
TL;DR: In this article, the role of aldosterone in podocyte injury has been explored in diabetic nephropathy (DN) and showed that mineralocorticoid receptor (MCR) blocker reduces proteinuria.
Journal ArticleDOI
Mineralocorticoid receptor antagonists in diabetic kidney disease - mechanistic and therapeutic effects.
Jonatan Barrera-Chimal,Ixchel Lima-Posada,George L. Bakris,Frederic Jaisser,Frederic Jaisser +4 more
TL;DR: In this paper, a large FIDELIO-DKD clinical trial showed that the non-steroidal MRA finerenone also slowed CKD progression and reduced the risk of adverse cardiovascular outcomes compared with placebo in patients with Type 2 diabetes.
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.