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.Univ Louisville, Kidney Dis Program, Core Proteom Lab, Dept Med, Louisville, KY 40202 USAUniv Louisville, Dept Pediat, Kosair Childrens Hosp Res Inst, Louisville, KY 40202 USAUniv Louisville, Dept Pharmacol & Toxicol, Louisville, KY 40202 USAUniv Louisville, Dept Biochem & Mol Biol, Louisville, KY 40202 USAMax Delbruck Ctr Mol Med, Berlin, GermanyEscola Paulista Med, Dept Biophys, São Paulo, BrazilMed Univ S Carolina, Dept Med, Charleston, SC 29425 USAMed Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USAVet Adm Med Ctr, Louisville, KY 40202 USAEscola Paulista Med, Dept Biophys, São Paulo, BrazilWeb of Scienc