Time- and dose-dependent effects of protein kinase C on proximal bicarbonate transport

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Abstract
Activation of protein kinase C has been shown to cause both stimulation and inhibition of transport processes in the brush-border membrane and renal tubule. This study was designed to examine the dose-response nature and time-dependent effect of 4 β-phorbol-12-myristate-13-acetate (PMA) on the rates of bicarbonate absorption (J HCO3) and fluid absorption (J v) in the proximal convoluted tubule (PCT) of rat kidney. Bicarbonate flux was determined by total CO2 changes between the collected fluid and the original perfusate as analyzed by microcalorimetry. Luminal perfusion of PMA (10−10 ≈ 10−5 M) within 10 min caused a significant increase ofJ HCO3 andJ v. A peaked curve of the dose response was observed with maximal effect at 10−8 M PMA on both bicarbonate and fluid reabsorption, which could be blocked completely by amiloride (10−3 m) and EIPA (10−5 M). On the other hand, with an increase of perfusion time beyond 15 min, PMA (10−8 and 10−6 M) could inhibitJ HCO3 andJ v. Amiloride (10−3 M) or EIPA (10−5 M) significantly inhibitsJ HCO3 andJ v, while there is no additive effect of PMA and amiloride or EIPA on PCT transport. An inactive phorbol-ester, 4α-phorbol, that does not activate protein kinase C, had no effects onJ HCO3 andJ v. Capillary perfusion of PMA (10−8 M) significantly stimulate bothJ HCO3 andJ v; however, PMA did not affect glucose transport from either the luminal side or basolateral side of the PCT. These results indicate that activation of endogenous protein kinase C by PMA could either stimulate or inhibit both bicarbonate and fluid reabsorption in the PCT dependent on time and dose, and these effects are through the modulation of Na+/H− exchange mechanism.