Published Online
on August 7, 2006

A more recent version of this article appeared on September 1, 2006

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Submitted on March 27, 2006
Revised on April 16, 2006

Superoxide Stimulates NaCl Absorption in the Thick Ascending Limb Via Activation of Protein Kinase C

Guillermo B. Silva; Pablo A. Ortiz; Nancy J. Hong; and Jeffrey L. Garvin

From the Division of Hypertension and Vascular Research (G.B.S., P.A.O., N.J.H., J.L.G.), Henry Ford Hospital, Detroit, Mich; and the Department of Physiology (J.L.G.), School of Medicine, Wayne State University, Detroit, Mich.

Abstract--Abnormal production of superoxide (O₂^-) contributes to hypertension, in part because of its effects on the kidney. The thick ascending limb absorbs 20% to 30% of the filtered load of NaCl. O₂^- stimulates NaCl absorption by the thick ascending limb by enhancing Na⁺/K⁺/2Cl^- cotransporter activity; however, the signaling mechanism is unknown. We hypothesized that O₂^- stimulates NaCl absorption by activating protein kinase C (PKC). To test this, we measured the effect of O₂^- on: (1) Cl^- absorption in the presence and absence of PKC inhibitors, (2) total PKC activity, and (3) activation of specific PKC isoforms. Isolated perfused medullary thick ascending limbs were exposed to O₂^- generated by xanthine oxidase (1 mU/mL) and hypoxanthine (0.5 mmol/L). O₂^- increased Cl^- absorption by 42% (from 76.2±3.6 to 108.2±11.9 pmol/min per millimeter; n=5; P<0.05). After treatment with the general PKC inhibitor staurosporine (10 nmol/L), O₂^- did not stimulate Cl^- absorption (-5.7±8.6%; n=6). In thick ascending limb suspensions, O₂^- increased total PKC activity by 33% (from 66±11 to 88±12 mU/mg protein; n=5; P<0.05) and increased PKC- and PKC- activity by 1.75- and 0.37-fold, respectively. The PKC-/-selective inhibitor Gö976 (100 nmol/L) blocked the ability of O₂^- to stimulate Cl^- absorption by isolated perfused medullary thick ascending limbs (4.5±15.0%; n=5). The role of PKC- could not be studied because of cell necrosis caused by the selective inhibitor rottlerin. We conclude that PKC- is required for O₂^--stimulated NaCl absorption in the thick ascending limb.

Key words: ion transport • kidney

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