Carvedilol through ß1-Adrenoceptor blockade ameliorates glomerulonephritis via inhibition of oxidative stress, apoptosis, autophagy, ferroptosis, endoplasmic reticulum stress and inflammation

Abstract

Glomerulonephritis (GN) is one of the main causes of end stage renal disease and requires an effective treatment for inhibiting GN. Renal nerves through efferent (RENA) and afferent (RANA) innervation to glomeruli regulate the glomerular function. We delineated the role of RENA and RANA on anti-Thy1.1-induced GN. Female Wistar rats were divided into Control, Thy1.1 plus anti-Thy1.1, bilaterally renal nerve denervation (DNX) plus anti-Thy1.1, and topical capsaicin to bilateral renal nerves for selective ablation of RANA (DNAX) plus anti-Thy1.1. We examined RANA and RENA response to anti-Thy1.1 and compared the effect of DNX or DNAX on urinary oxidative stress, renal gp91, tyrosine hydroxylase (TH), calcitonin gene-related peptide (CGRP), apoptosis, autophagy, ferroptosis, antioxidant enzymes, endoplasmic reticulum (ER) stress and inflammation by western blot. Anti-Thy1.1 significantly enhanced RENA, but did not affect RANA. DNX significantly decreased TH and CGRP expression, whereas DNAX only reduced CGRP expression. Anti-Thy1.1 significantly increased glomerulosclerosis injury, urinary protein, electron paramagnetic resonance signals of alpha-(4-pyridyl-N-oxide)-N-tert-butylnitrone adducts, 8-isoprostane and nitrotyrosine levels, NADPH oxidase gp91phox (gp91), macrophage/monocyte (ED-1), GRP-78, Beclin-1/LC3-II, Bax/caspase-3/poly(ADP-ribose) polymerase expression, inflammatory cytokines levels and decreased renal Copper/Zinc superoxide dismutase, Cystine/glutamate transporter (xCT) and Glutathione peroxidase 4 (GPX4) expression vs. Control. The enhanced oxidative parameters or reduced antioxidant defense by anti-Thy1.1 were significantly attenuated by DNX but not DNAX. Additionally, oral ß1-adrenoceptor antagonist-Carvedilol at an early stage reduced anti-Thy1.1 increased proteinuria level and oxidative parameters. Our data suggest that DNX and ß1-adrenoceptor antagonist-Carvedilol efficiently attenuate oxidative stress, inflammation, ER stress, autophagy, ferroptosis and apoptosis in GN.