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Hypertension‐Induced Renal Injury is Associated with Impaired Glomerular Barrier Function Involving Podocyte Dysfunction
Author(s) -
He Xiaochen,
Chen Chun Cheng Andy,
Murphy Sydney R.,
Booz George W.,
Roman Richard J.,
Fan Fan
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.573.9
Subject(s) - medicine , endocrinology , podocyte , renal function , chemistry , tubuloglomerular feedback , afferent arterioles , proteinuria , kidney , glomerulosclerosis , blood pressure , renin–angiotensin system
Dahl SS rats rapidly develop hypertension, proteinuria, and renal injury when challenged with a high‐salt diet. Previous studies revealed that a deficiency in the renal formation of 20‐HETE in SS rats impairs afferent arteriole myogenic response, autoregulation of renal blood flow, tubuloglomerular feedback and glomerular capillary pressure and enhances sodium transport in the thick ascending loop of Henle. However, the role of 20‐HETE in podocyte and glomerular barrier function is still unknown. The aim of this study is to investigate the role of 20‐HETE on the regulation of glomerular function and podocyte function using SS rats and CYP4A1 transgenic rats on a SS background. We found that the production of 20‐HETE was significantly higher in the isolated glomeruli of CYP4A1 compared to SS rats by using mass spectrometry. Immunoblot analysis demonstrated that the expression of α‐smooth muscle actin and vimentin was lower in the isolated glomeruli of CYP4A1 vs. SS rats, indicating reduced epithelial mesenchymal transition (EMT). After challenged with a 4% high‐salt diet, the mean arterial pressure increased to a similar extent in both strains as measured by radio telemetry. However, compared with SS rats, CYP4A1 rats developed lower proteinuria (127 ± 14 vs. 270 ± 23 mg/day, respectively), had unaltered glomerular permeability to albumin (Palb) by using a fluorescence dilution technique, and exhibited greater increases in Palb after treatment with HET0016, a 20‐HETE synthesis inhibitor. In addition, Masson's trichrome staining showed that the glomerular injury score was attenuated in hypertensive CYP4A1 transgenic vs. SS rats (1.3 ± 0.2 vs. 2.4 ± 0.2, respectively), and the area of renal interstitial fibrosis was significantly lower in CYP4A1 transgenic vs. SS rats (6% ± 1% vs. 18% ± 4%, respectively). Moreover, hypertensive CYP4A1 rats exhibited less podocyte foot process effacement and detachment than SS rats when examined by a transmission electron microscopy. These findings indicate that increased production of 20‐HETE has renoprotective effects in association with decreased EMT, preserved podocyte and glomerular barrier function. This study indicates that 20‐HETE is a potential novel pharmacological target and biomarker in hypertension and chronic kidney disease. Support or Funding Information This study was supported by grants HL36279 (RJR) and DK104184 (RJR), AG050049 (FF), P20GM104357 (RJR and FF) from the National Institutes of Health; 16GRNT31200036 (FF) from the American Heart Association. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .