The bradykinin B 1 -receptor is strongly upregulated under chronic inflammatory conditions. However, the mechanism and reason are not known. Because a better understanding of the mechanism of the upregulation will help in understanding its potential importance in inflammation, we have studied the molecular mechanism of B 1 -receptor upregulation in cultured human lung fibroblasts (

In the rat mesangial cell (MC), activation of the bradykinin B2 receptor (B2R) by bradykinin (BK) is associated with both phospholipase C (PLC) and A2(PLA2) activities and with inhibition of adenosine 3′,5′-cyclic monophosphate (cAMP) formation leading to cell contraction. Because cAMP plays an important role in the regulation of gene expression in general, we investigated the effect of increasing the intracellular cAMP concentration ([cAMP]i) in mesangial cells on the B2 mRNA expression, on the density of B2receptor binding sites, on the BK-induced increase in both the free cytosolic Ca2+ concentration ([Ca2+]i), and in the prostaglandin E2(PGE2) production. Forskolin, PGE2, and cAMP analog, 8-bromoadenosine 3′,5′-cyclic monophosphate (8-BrcAMP), were used to increase [cAMP]i. Twenty-four-hour treatment with forskolin, PGE2, and 8-BrcAMP resulted in significant increases in B2receptor binding sites, which were inhibited by cycloheximide. The maximum B2 receptor mRNA expression (160% above control) was observed in cells treated during 24 h with forskolin and was prevented by actinomycin D. In contrast, thed- myo-inositol 1,4,5-trisphosphate (IP3) formation and the BK-induced increase in [Ca2+]i, reflecting activation of PLC, were not affected by increased levels of [cAMP]i. However, the BK-induced PGE2 release, reflecting PLA2 activity, was significantly enhanced. These data bring new information regarding the dual signaling pathways of B2receptors that can be differentially regulated by cAMP.

During the course of aging, the balance between intrarenal hormones is disturbed. These age-related changes are well documented for the vasoconstrictor renin-angiotensin system, but comparable information on the renal kallikrein-kinin system is not yet available. The status of the kallikrein-kinin system was assessed by (1) kallikrein activity, measured by RIA; (2) maximum binding site density (Bmax) and affinity (Kd) of nonapeptide bradykinin (BK)-2 receptor, estimated by binding assays; (3) expression of BK2-receptor receptor mRNA, detected by reverse transcription-polymerase chain reaction (RT-PCR) using specific BK2-oligonucleotide primers. These parameters were determinated on renal glomeruli of 3-, 5-, 8-, 12- and 38-wk-old normotensive rats. Kallikrein activity increased from 3.2 to 7.7 ng BK/min per mg protein. The density of BK2 binding sites also rose from 12 to 40 femtomoles/mg protein with no difference in affinity. There was no change in specificity, which remained that expected of a BK2 receptor. The increase in the density of BK2 binding sites was associated with an augmented mRNA expression, whereas beta-actin mRNA used as a control remained unchanged. The ratio of BK2 mRNA to beta-actin mRNA indicated maximum steady expression after 8 wk of age. The data provide evidence that the renal kallikrein-kinin system develops postnatally.