Global upregulation of gene expression associated with renal dysfunction in DOCA-salt-induced hypertensive rats occurs via signaling cascades involving epidermal growth factor receptor: a microarray analysis.
Renal dysfunction is a major cause of morbidity and mortality in patients with hypertension. In an attempt to understand the molecular mechanisms leading to renal dysfunction and in particular that of epidermal growth factor receptor (EGFR) and RasGTPase signaling, we analyzed global gene expression changes in the kidneys of deoxycorticosterone acetate (DOCA)-salt-induced hypertensive rats with and without treatment with AG1478, a selective inhibitor of EGFR tyrosine kinase, or FPTIII, a farnesyl transferase inhibitor known to inhibit RasGTPase. Microarray-based global gene expression analysis was performed in triplicate for each rat kidney taken from normotensive Wistar rats, DOCA-salt hypertensive (DH) rats, DH rats treated with AG1478, or DH rats treated with FPTIII. From the initial data set of 10,163 gene spots per group, upregulation of 2398 genes and downregulation of only 50 genes by more than 2-fold was observed in hypertensive rat kidneys compared to non-diseased controls. Interestingly, treatment of animals with AG1478 or FPTIII prevented upregulation of more than 97% of genes associated with hypertension in the rat kidney. Analysis of proteinuria, renal artery responsiveness and histopathology studies confirmed that DOCA-salt hypertensive rats had developed kidney damage over the study period and that this kidney dysfunction could be significantly prevented upon AG1478 or FPTIII treatment without normalising blood pressure. Taken together, our data imply that signaling cascades involving EGFR and/or RasGTPase pathways are key contributors to the induction of renal damage in hypertension and these and potentially other downstream effector molecules may serve as novel targets for therapeutic intervention.
Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, PO Box 24923, Safat 13110, Kuwait. ibenter@hsc.edu.kw
Ibrahim F
IF
Benter
Halit
H
Canatan
Mustapha
M
Benboubetra
Mariam H M
MH
Yousif
Saghir
S
Akhtar
D000818:Animals; D003900:Desoxycorticosterone / Q000031:analogs & derivatives; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D005786:Gene Expression Regulation; D006973:Hypertension / Q000139:chemically induced / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D020559:Monomeric GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D063065:Organophosphonates / Q000494:pharmacology; D011799:Quinazolines; D051381:Rats; D017208:Rats, Wistar; D012077:Renal Artery / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction; D012965:Sodium Chloride; D020032:Tyrphostins / Q000008:administration & dosage / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
C436083:2-(2-oxo-2-((3,7,11-trimethyl-2,6,10-dodecatrienyl)oxy)aminoethyl)phosphonic acid, (2,2-dimethyl-1-oxopropoxy)methyl ester sodium; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D051231:Farnesyltranstransferase; D066246:ErbB Receptors; D020559:Monomeric GTP-Binding Proteins