Elevated (Pro)renin Receptor Expression Contributes to Maintaining Aerobic Metabolism in Growth Hormone Deficiency

CONTEXT: Growth hormone deficiency (GHD) leads to obesity and may induce tissue hypoxia. As (pro)renin receptor [(P)RR] is reported to contribute to the aerobic metabolism by stabilizing pyruvate dehydrogenase (PDH), it may play a substantial role in GHD. OBJECTIVE: We aimed to investigate serum soluble (P)RR [s(P)RR] concentration, the origin of s(P)RR, and significance of (P)RR in GHD. DESIGN, SETTING, AND PARTICIPANTS: Serum s(P)RR concentration was examined in 72 patients with pituitary diseases, including 32 patients with severe GHD (SGHD) and after GH replacement in 16 SGHD patients. Leptin-deficient ob/ob obese mice were treated with pegvisomant, a GH receptor antagonist, to explore the source of elevated serum s(P)RR in GHD. Adipocytes were cultured with 5% O(2) to examine the effects of hypoxia. RESULTS: Serum s(P)RR concentration was higher in patients with SGHD than in those without SGHD. Obesity was the important determinant of s(P)RR concentration. Serum s(P)RR concentration significantly decreased after GH replacement in SGHD patients. (P)RR mRNA expression was increased specifically in the adipose tissue (AT) of pegvisomant-treated obese mice compared with that of control obese mice. Hypoxia in cultured adipocytes increased (P)RR expression without affecting the PDH E1 β subunit (PDHB) expression; however, with (P)RR knockdown by small interfering RNA, hypoxia significantly decreased the expression of PDHB. CONCLUSION: GHD patients showed increased serum s(P)RR concentration, possibly caused by obesity and hypoxia. (P)RR expression in AT of GHD patients may be elevated to help maintain aerobic metabolism under hypoxia. Thus, the elevated serum s(P)RR level may reflect hypoxia in ATs.