Uric acid inhibits renal proximal tubule cell proliferation via at least two signaling pathways involving PKC, MAPK, cPLA2, and NF-κB
Uric acid inhibits renal proximal tubule cell proliferation via at least two signaling pathways involving PKC, MAPK, cPLA2, and NF-κB
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DOI：
10.1152/ajprenal.00104.2006
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发表时间：
2007-01-01
影响因子：
4.2
通讯作者：
Taub, Mary
中科院分区：
文献类型：
--
作者：
Han, Ho Jae;Lim, Min Jin;Taub, Mary
尿酸是嘌呤代谢的终产物，尿酸的积累导致痛风性关节炎中观察到的许多有害作用，包括肾损伤。在此，我们提供了证据表明，在高尿酸血症（> 10（-4）M尿酸）的条件下，[H-3]胸苷掺入原代肾近曲小管细胞（PTC）受到抑制，我们描绘了相关的信号通路。观察到尿酸升高刺激MAPK磷酸化。尿酸诱导的p38 MAPK磷酸化也被H-7（PKC抑制剂）阻断，表明p38 MAPK是PKC的下游靶点。细胞质磷脂酶A（2）（cPLA 2）参与下游的证据包括：1）尿酸对[H-3]-标记的花生四烯酸（AA）释放的刺激作用：2）尿酸对AA释放的刺激作用可被PKC抑制剂H-7和p38 MAPK抑制剂SB 203580阻断; SB 203580以及cPLA 2抑制剂花生四烯酸三氟甲基酮和mepacrine（另一种PLA 2抑制剂）阻止尿酸诱导的[H-3]胸苷掺入抑制。获得了尿酸诱导的NF-κ B和PLA 2活化的证据。此外，尿酸诱导的[H-3]胸苷掺入抑制也被两种NF-κ B抑制剂吡咯烷二硫代氨基甲酸酯和SN 50阻断。但SN 50不能阻断尿酸诱导的[H-3] AA释放.因此，尿酸对[H-3]胸苷掺入的抑制可以通过两种不同的机制来解释，即NF-κ B的激活以及PLA 2的激活。
The accumulation of uric acid, an end-product of purine metabolism, is responsible for the many deleterious effects observed in gouty arthritis, including renal injury. Here, we present evidence that under conditions of hyperuricemia (> 10(-4) M uric acid) [H-3] thymidine incorporation into primary renal proximal tubule cells (PTCs) is inhibited, and we delineate the signaling pathways involved. Elevated uric acid was observed to stimulate MAPK phosphorylation. The uric acid induced p38 MAPK phosphorylation was also blocked by H-7 (a PKC inhibitor), indicating that p38 MAPK was a downstream target of PKC. Evidence that cytoplasmic phospholipase A(2) (cPLA2) was involved further downstream included 1) the stimulatory effect of uric acid on [H-3]-labeled arachidonic acid (AA) release; 2) the stimulation of AA release in response to uric acid was blocked by the PKC inhibitor H-7 as well as by the p38 MAPK inhibitor SB 203580; and 3) the uric acid-induced inhibition of [H-3] thymidine incorporation was prevented by SB 203580, as well as by the cPLA2 inhibitor arachidonyl trifluoromethyl ketone, and mepacrine (another PLA2 inhibitor). Evidence of a uric acid-induced activation of NF-kappa B as well as PLA2 was obtained. Moreover the uric acid-induced inhibition of [H-3] thymidine incorporation was also blocked by two NF-kappa B inhibitors, pyrrolidine dithiocarbamate and SN 50. However, SN 50 did not block the uric acid induced [H-3] AA release. Thus the inhibition of [H-3] thymidine incorporation caused by uric acid can be explained by two distinct mechanisms, the activation of NF-kappa B as well as the activation of PLA2.