Uric acid inhibits renal proximal tubule cell proliferation via at least two signaling pathways involving PKC, MAPK, cPLA₂, and NF-κB

Abstract

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) [(3)H]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) (cPLA(2)) was involved further downstream included 1) the stimulatory effect of uric acid on [(3)H]-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 [(3)H]thymidine incorporation was prevented by SB 203580, as well as by the cPLA(2) inhibitor arachidonyl trifluoromethyl ketone, and mepacrine (another PLA(2) inhibitor). Evidence of a uric acid-induced activation of NF-kappaB as well as PLA(2) was obtained. Moreover the uric acid-induced inhibition of [(3)H]thymidine incorporation was also blocked by two NF-kappaB inhibitors, pyrrolidine dithiocarbamate and SN 50. However, SN 50 did not block the uric acid induced [(3)H]AA release. Thus the inhibition of [(3)H]thymidine incorporation caused by uric acid can be explained by two distinct mechanisms, the activation of NF-kappaB as well as the activation of PLA(2).

Albumin-stimulated DNA synthesis is mediated by Ca2+/PKC as well as EGF receptor-dependent p44/42 MAPK and NF-κB signal pathways in renal proximal tubule cells

“…PTCs have a number of differentiated typical functions of the renal proximal tubules, including a polarized morphology, as well as a distinctive proximal tubule transport and hormone response (9,17). It was previously reported that the ATPincreased cell proliferation in primary cultured PTCs is consistent with the results obtained from intact renal tissue (23,24).…”

Noncrystalline uric acid inhibits proteoglycan and glycosaminoglycan synthesis in distal tubular epithelial cells (MDCK)

“…It was shown that UrAc stimulates COX-2 expression and activation and prostaglandin synthesis (18). In the present study, we observed that UrAc crystals induced COX-2 expression and PGE2 production (19). Nevertheless, the effect of UrAc on the synthesis of GAGs and proteoglycans could not be related to its inflammatory actions, since LPS, a well known inflammatory agent, did not decrease GAG synthesis.…”

“…On the other hand, in the renal system, the mechanisms described for UrAc effects on proximal epithelial tubular cells include NF-kB, protein kinase C, MAPK and cPLA2 (19). In the present study, we tested the hypothesis that COX-2 activation and its synthesis product prostaglandin could be related to the effect of noncrystalline UrAc in these cells.…”

“…Soluble UrAc also has proinflammatory and deleterious effects on endothelial, vascular smooth muscle and proximal tubular cells such as proliferation, activation of mitogen-activated protein kinases (MAPK), chemokines (monocyte chemoattractant protein-1), and the inflammatory enzymes cyclooxygenase 2 (COX-2) and prostaglandins (19).…”

Onco-Nephrology

“…Vascular smooth muscle cells exposed to dissolved uric acid release the inflammatory cytokines monocyte chemotactic protein-1, TNF-a, and other vasoactive mediators, leading to chemotaxis of white cells and further inflammatory injury (20). Finally, uric acid may inhibit proximal tubule cell proliferation, prolonging the duration of kidney injury (21).…”