Cardiotonic steroids (CTS), including ouabain and marinobufagenin, have a natriuretic effect through their action on the Na+/K+-ATPase in the kidney. In addition to a role in inducing salt-sensitive hypertension, they are also implicated in insulin regulation. CarcinoEmbryonic Antigen Cell Adhesion Molecule (CEACAM) protein, a known mediator of insulin clearance via its interaction with the insulin receptor (IR), among its other functions, is also expressed in the kidney, and involved in the development of insulin resistance. We investigate a possible interaction between cardiotonic steroids and insulin in signaling through the sodium pump toward the development of insulin resistance and salt-sensitive hypertension. The sodium pump, insulin receptor, epidermal growth factor receptor (EGFR), and CEACAM1 are expressed on the basolateral aspect of polarize renal proximal tubule LLC-PK1 cells, where they can interact to facilitate intracellular signaling. Cardiotonic steroids and insulin, both of which can signal through the Na+/K+-ATPase, stimulated decreased plasmalemmal expression, with corresponding increase in early endosomal accumulation, of CEACAM1 protein. EGFR and IR showed similar changes with exogenous ouabain or insulin stimulation, though these changes were not synergistic. Thus, in addition to its role in insulin clearance in the liver, CEACAM1 could also play a role in cardiotonic steroid-induced natriuresis and salt-sensitive hypertension in the kidney. This was supported by increased salt-sensitive hypertension in those mice lacking CEACAM2, a homologous and possibly functionally redundant protein present along with CEACAM1 in mice.
If as predicted, the incidence of diabetes does indeed increase in the future, associated diseases such as chronic renal failure may also have a greater impact. Taken together, these data provide molecular insight into a well-documented clinical association between chronic renal failure and insulin resistance. CEACAM, in addition to its extensively studied role in hepatic insulin clearance, is revealed as a novel player and potential therapeutic target in mediating the effects of increased cardiotonic steroids, as observed in patients with chronic renal failure, via the sodium pump.