Ceramide-activated protein kinases A and C zeta inhibit kidney proximal tubule cell Na-ATPase

The basolateral membranes of kidney proximal tubule cells have (Na⁺+K⁺)-ATPase and Na⁺-ATPase activities, involved in Na⁺ reabsorption. We showed that ceramide (Cer) modulates protein kinase A (PKA) and protein kinase C (PKC), which are involved in regulating ion transporters. Here we show that ceramide, promotes 60% inhibition of Na⁺-ATPase activity (I₅₀ ≈ 100 nM). This effect was completely reversed by inhibiting PKA but did not involve the classic PKC signaling pathway. In these membranes we found the Cer-activated atypical PKC zeta (PKCζ) isoform. When PKCζ is inhibited, Cer ceases to inhibit the Na⁺-ATPase, allowing the cAMP/PKA signaling pathway to recover its stimulatory effect on the pump. There were no effects on the (Na⁺+K⁺)-ATPase. These results reveal Cer as a potent physiological modulator of the Na⁺-ATPase, participating in a regulatory network in kidney cells and counteracting the stimulatory effect of PKA via PKCζ.