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Signaling cascade of ANG II-induced inhibition of -MG uptake in renal proximal tubule cells

Department of Veterinary Physiology, College of Veterinary Medicine, Hormone Research Center, Chonnam National University, Gwangju 500-757, Korea

Submitted 10 June 2003 ; accepted in final form 10 November 2003

ANG II and Na⁺-glucose cotransporter have been reported to be associated with the onset of diverse renal diseases. However, the effect of ANG II on Na⁺-glucose cotransporter activity was not elucidated. The effects of ANG II on -methyl-D-[¹⁴C]glucopyranoside (-MG) uptake and its related signal pathways were examined in the primary cultured rabbit renal proximal tubule cells (PTCs). ANG II (>2 h; >10^-9 M) inhibited -MG uptake in a time- and concentration-dependent manner and decreased the protein level of Na⁺-glucose cotransporters, the expression of which was abrogated by both actinomycin D and cycloheximide exposure. ANG II-induced inhibition of -MG uptake was blocked by losartan, an ANG II type 1 (AT₁) receptor blocker, but not by PD-123319, an ANG II type 2 receptor blocker. ANG II-induced inhibition of -MG uptake was blocked by genistein, herbimycin A [tyrosine kinase (TK) inhibitors], mepacrine, and AACOCF₃ (phospholipase A₂ inhibitors), suggesting the role of TK phosphorylation and arachidonic acid (AA). Indeed, ANG II increased AA release, which was blocked by losartan or TK inhibitors. The effects of ANG II on AA release and -MG uptake also were abolished by staurosporine and bisindolylmaleimide I (protein kinase C inhibitors) or PD-98059 (p44/42 MAPK inhibitor), but not SB-203580 (p38 MAPK inhibitor), respectively. Indeed, ANG II increased p44/42 MAPK activity. ANG II-induced activation of p44/42 MAPK was blocked by staurosporine. In conclusion, ANG II inhibited -MG uptake via PKC-MAPK-cPLA₂ signal cascade through the AT₁ receptor in the PTCs.

angiotensin II; kidney; mitogen activated protein kinase; phospholipase A₂; protein kinase C; sodium ion-glucose cotransporter; -methyl-D-[¹⁴C]glucopyranoside

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