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Intestinal inflammation induces functional Na+/H+ exchanger 3 defect via downregulation of PDZ‐domain adaptor protein PDZK1 (NHERF3)

Intestinal inflammation results in loss of sodium absorptive function and diarrhea. The present study investigates a potential causal relationship between the inflammation‐induced reduction in expression levels of the PDZ‐adaptor protein PDZK1 and decreased functional activity of its binding partner Na+/H+ exchanger NHE3. Expression of PDZK1 mRNA and protein was found strongly decreased in inflamed intestinal mucosa of murine colitis models, in colonic mucosa of patients with active ulcerative colitis, and in Caco‐2bbe cells treated with Th1 proinflammatory cytokines. Acid‐activated NHE3 transport activity as well as its inhibition by forskolin (FSK) was assessed fluorometrically in microdissected murine and human BCECF‐loaded ileal villi and colonic crypts. The decrease in acid‐activated NHE3 activity and loss of FSK inhibition was similar in PDZK1 +/− enterocytes, in which PDZK1 protein content was reduced by >; 50%, than in inflamed enterocytes, suggesting a causal relationship between PDZK1 downregulation and NHE3 dysfunction, independent of inflammation. Likewise, ShRNA‐mediated PDZK1 knockdown in Caco2bbe resulted in a significant decrease in NHE3 membrane abundance, transport activity and FSK inhibition. We conclude that the marked decrease in the PDZ‐adaptor protein PDZK1 in inflamed murine and human enterocytes is causally related to inflammation‐associated NHE3 dysfunction.