| 25230 |
Q62847 |
ADDG_RAT |
Gamma-adducin (Adducin-like protein 70) (Protein kinase C-binding protein 35H) |
DISRUPTION PHENOTYPE |
Renal afferent arteriole (Af-art) of the Dicer-substrate short interfering RNA (DsiRNA) knockdown rats dilates instead of constricts as the wild-type vessel in response to an elevation in perfusion pressure. Knockdown results in impaired myogenic response in the middle cerebral artery (MCA), but vasoconstrictor response to serotonin is not affected in the presence of iberiotoxin (IBTX). Knockdown has no effect on the vasoconstrictor response of the renal Af-art to norepinephrine. Smooth muscle cells isolated from the renal microvessels or MCAs of the knockdown rats have higher peak potassium currents than the wild-type cells. A significantly higher level of IBTX-sensitive peak potassium current densities are detected in smooth muscle cells of the cerebral microvessels of the knockdown rats (PubMed:27927653). Knockout rats have elevated iberiotoxin-sensitive potassium (BK) channel current in renal vascular smooth muscle cells (VSMCs) and exhibit impairments in the myogenic response of Af-arts (PubMed:32029431). Renal blood flow (RBF) autoregulation is also impaired (PubMed:32830539, PubMed:32029431). Knockout rats have decreased glomerular capillary pressure in response to elevated blood pressure. After 1 week of DOCA-salt induced hypertension the glomerular filtration rate (GFR) increases and glomerular nephrin expression decreases while they remain unchanged in wild-type rats. Myogenic response is impaired in interlobular arteries of the knockout rats. Proteinuria, glomerulosclerosis and renal interstitial fibrosis are more pronounced in knockout rats after 3 weeks of hypertension compared to wild-type rats. Expression of macrophage-related proinflammatory cytokines, infiltrating CD68(+) macrophages and the markers of epithelial mesenchymal transition increase after hypertension. These alterations in hypertensive knockout rats lead to increased transmission of pressure to glomeruli inducing podocyte loss, and accelerated progression of chronic kidney disease (CKD) (PubMed:32830539). Acute administration of N(G)-nitro-L-arginine methyl ester (L-NAME) raises mean arterial pressure (MAP) of the knockout rats as in wild-type, but RBF and GFR are decreased less in knockout rats. However, RBF and GFR are significantly greater in knockout rats than in wild-type after the simultaneous administration of L-NAME and furosemide. Chronic administration of L-NAME with a simultaneous high-salt diet leads to impaired renal vasoconstrictor response to the blockade of nitric oxide synthase, which promotes hypertension-induced proteinuria and renal injury in knockout rats. After chronic administration of L-NAME, MAP increases in the knockout rats the same way as in wild-type, but RBF, GFR and glomerular capillary pressure are increased. They have greater loss of podocytes and glomerular nephrin expression than wild-type rats, and increased renal interstitial fibrosis. Expression of the profibrotics markers MMP9, MMP2 and TGF beta-1 increases more in L-NAME-treated knockout rats than in wild-type rats. Expression of tubular tight junction protein E-cadherin decreases more in knockout rats treated with L-NAME and high-salt diet for 3 weeks in association with greater expression of mesenchymal markers vimentin and alpha-SMA compared to wild-type (PubMed:33414130). {ECO:0000269|PubMed:27927653, ECO:0000269|PubMed:32029431, ECO:0000269|PubMed:32830539, ECO:0000269|PubMed:33414130}. |