Proteomic analysis reveals alterations in the renal kallikrein pathway during hypoxia-induced hypertension.
Obstructive sleep apnea syndrome (OSAS), a disorder characterized by episodic hypoxia (EH) during sleep, is associated with systemic hypertension. We used proteomic analysis to examine differences in rat kidney protein expression during EH, and their potential relationship to EH-induced hypertension. Young male Sprague-Dawley rats were exposed to either EH or sustained hypoxia (SH) for 14 (EH14/SH14) and 30 (EH30/SH30) days. Mean arterial blood pressure was significantly increased only in EH30 (p < 0.0002). Kidney proteins were resolved by two-dimensional-PAGE and were identified by MALDI-MS. Renal expression of kallistatin, a potent vasodilator, was down-regulated in all animals. Expression of alpha-1-antitrypsin, an inhibitor of kallikrein activation, was up-regulated in EH but down-regulated in SH. Western blotting showed significant elevation of B(2)-bradykinin receptor expression in all normotensive animals but remained unchanged in hypertensive animals. Proteins relevant to vascular hypertrophy, such as smooth muscle myosin and protein-disulfide isomerase were up-regulated in EH30 but were down-regulated in SH30. These data indicate that EH induces changes in renal protein expression consistent with impairment of vasodilation mediated by the kallikrein-kallistatin pathway and vascular hypertrophy. In contrast, SH-induced changes suggest the kallikrein- and bradykinin-mediated compensatory mechanisms for prevention of hypertension and vascular remodeling. To test the hypothesis suggested by the proteomic data, we measured the effect of EH on blood pressure in transgenic hKLK1 rats that overexpress human kallikrein. Transgenic hKLK1 animals were protected from EH-induced hypertension. We conclude that EH-induced hypertension may result, at least in part, from altered regulation of the renal kallikrein system.
Core Proteomics Laboratory, Kidney Disease Program, Department of Medicine, University of Louisville, Louisville, Kentucky 40202, USA. visith.thongboonkerd@louisville.edu
Visith
V
Thongboonkerd
Evelyne
E
Gozal
Leroy R
LR
Sachleben
John M
JM
Arthur
William M
WM
Pierce
Jian
J
Cai
Julie
J
Chao
Michael
M
Bader
Joao B
JB
Pesquero
David
D
Gozal
Jon B
JB
Klein
D000595:Amino Acid Sequence; D000818:Animals; D001794:Blood Pressure; D015180:Electrophoresis, Gel, Two-Dimensional; D006973:Hypertension / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications*; D007610:Kallikreins / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D020543:Proteome; D051381:Rats; D017207:Rats, Sprague-Dawley; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D020543:Proteome; D007610:Kallikreins