Erlotinib preserves renal function and prevents salt retention in doxorubicin treated nephrotic rats.
Nephrotic syndrome is associated with up-regulation of the heparin-binding epidermal growth factor (HB-EGF). Erlotinib blocks the activation of the epidermal growth factor receptor (EGFR) in response to HB-EGF. This study investigates the effect of Erlotinib on the progression of proteinuria, renal dysfunction, and salt retention in doxorubicin treated nephrotic rats. Male rats were divided into 3 pair-fed groups (n = 13/group) as follows: Control rats (Ctrl); rats receiving intravenous doxorubicin (Dox); and rats receiving intravenous doxorubicin followed by daily oral Erlotinib (Dox + Erl). Upon establishment of high grade proteinuria, urine sodium and creatinine clearance were measured. Kidney tissue was dissected and analyzed for γ-epithelial sodium channel (γENaC), sodium-potassium -chloride co-transporter 2 (NKCC2), sodium chloride co-transporter (NCC), aquaporin 2 (AQP2), and EGFR abundances using western blot. Creatinine clearance was preserved in the Dox + Erl rats as compared to the Dox group (in ml/min: Ctrl: 5.2±.5, Dox: 1.9±0.3, Dox + Erl: 3.6±0.5). Despite a minimal effect on the degree of proteinuria, Erlotinib prevented salt retention (Urinary Na in mEq/d: Ctrl: 2.2±0.2, Dox: 1.8±0.3, Dox + Erl: 2.2±0.2). The cleaved/uncleaved γENaC ratio was increased by 41±16% in the Dox group but unchanged in the Dox + Erl group when compared to Ctrl. The phosphorylated EGFR/total EGFR ratio was reduced by 74±7% in the Dox group and by 77±4% in the Dox + Erl group. In conclusion, Erlotinib preserved renal function and prevented salt retention in nephrotic rats. The observed effects do not appear to be mediated by direct blockade of EGFR.
Department of Pediatric Medicine, Emory University, and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
Raed N
RN
Bou Matar
Janet D
JD
Klein
Jeff M
JM
Sands
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D051399:Aquaporin 2 / Q000378:metabolism; D003404:Creatinine / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity; D053503:Epithelial Sodium Channels / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D009404:Nephrotic Syndrome / Q000139:chemically induced / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011507:Proteinuria / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D011799:Quinazolines / Q000008:administration & dosage*; D051381:Rats; D051437:Renal Insufficiency / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D049992:Sodium Chloride Symporters / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1
D000903:Antibiotics, Antineoplastic; D051399:Aquaporin 2; D053503:Epithelial Sodium Channels; C587883:HBEGF protein, human; C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C578714:SLC12A1 protein, human; C578716:Slc12a1 protein, rat; D049992:Sodium Chloride Symporters; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D004317:Doxorubicin; D003404:Creatinine; D000069347:Erlotinib Hydrochloride; C483803:Egfr protein, rat; D066246:ErbB Receptors