In:
Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 72, No. Suppl_1 ( 2018-09)
Abstract:
We recently found that the G-protein coupled estrogen receptor (GPER) exerts constitutive effects on cell proliferation and fibrosis in heart failure and arterial hypertension via the NADPH oxidase isoform Nox1 (Sci Signal 2016; 9(452): ra105). Whether GPER affects glomerulosclerosis or podocyte function is unknown. Thus, the present study investigated the effects of GPER in a model of age-dependent spontaneous focal segmental glomerulosclerosis and studied effects of GPER inhibition in mesangial cells and podocytes. Albuminuria and kidney histology were studied in male wild-type (WT) and GPER-deficient ( Gper -/- ) mice at 4 and 24 months of age. Aged Gper -/- mice were largely protected from albuminuria (albumin/creatinine-ratio, 0.9±0.4 vs. 3.5±1.0, -74 %, p 〈 0.05 vs. WT). Gper deficiency had no effect at 4 months of age, but largely prevented age-dependent increases in kidney weight (306±11 vs. 554±94 mg), and glomerulosclerosis index (1.3±0.2 vs. 2.9±0.4, p 〈 0.05 vs. WT). All changes were independent of blood pressure. In human podocytes exposed to TGFβ-1, treatment with the selective GPER blocker G36 markedly reduced mRNA expression of injury markers nephrin, collagen-4, and Wilms-tumor-1 (all p 〈 0.01). Gper knock-down in rat mesangial cells reduced Nox1 protein expression by approx. 50% (p 〈 0.05) while Nox2 and Nox4 expression remained unchanged. These results indicate that constitutive activity of Gper maintains Nox1 expression and contributes to podocyte injury in vitro and that Gper is essential for age-dependent podocyte injury, subsequent albuminuria, fibrosis and glomerulosclerosis in vivo. Nox1 downregulators such as G36 represent a new class of drugs that may offer therapeutic potential for patients with chronic renal diseases and other forms of chronic non-communicable diseases involving inflammation and fibrosis.
Type of Medium:
Online Resource
ISSN:
0194-911X
,
1524-4563
DOI:
10.1161/hyp.72.suppl_1.P261
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2018
detail.hit.zdb_id:
2094210-2
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