Histamine regulates the activity and the expression of the Na+/H+ exchanger (NHE)3 in human epithelial HK-2 cells

Objective and design: Investigate the potential role of histamine and its receptors on the functional expression of the sodium/hydrogen (Na+/H+) exchanger (NHE)3. Material: The human epithelial kidney (HK-2) cells were used as an in vitro model of the renal proximal tubule. Treatment: HK-2 cells were exposed to histamine 0–1000 nM alone or in combination with chlorphenamine (10 μM) and JNJ-7777120 (1 μM) for 0–48 h. MAPK involvement was determined using the selective inhibitors SB202190 (p38 MAPK), PD98059 (ERK1/2), and SP600125 (SAPK/JNK). Methods: Gene and protein expression were evaluated by qPCR and immunoblotting. The activity of NHE3 was measured by the BCECF-AM-based method. Results: Histamine (100 nM) induced a concentration-dependent NHE3 gene transcription with a peak 16 h after the treatment, followed by protein translation at 48 h after. A Consistent increase in NHE3 activity was observed at 48 h, but also at 60 min, when both p38 MAPK and ERK1/2 were phosphorylated. JNJ-7777120 blunted the activation and expression of NHE3. Chlorpheniramine was effective only on NHE3 activity. Conclusions: Histamine shows early (within 60 min) and late (48 h) effects on NHE3 expression. The histamine H1 and H4 receptors are shown to contribute to these effects differentially. The findings of this study extends the evidence for a direct contribution of histamine on the renal reabsorptive machinery.