Acidic Eye‐Drops De‐Swell the Edematous Corneas of Slc4a11‐null Mice; Evidence for Functional Coupling between Slc4a11 and the H+/lactate Cotransporter Mct1
Authors: Myers Evan , Patel Sangita P , Marshall Aniko , Jennings Michael L , Parker Mark D 
Published: November 2023

SLC4A11 is the most divergent member of the SLC4 family of acid‐base transporters. Mutations in SLC4A11 are associated with congenital hereditary endothelial dystrophy (CHED): a clouding of the cornea caused by the accumulation of fluid in the corneal stroma. Slc4a11‐null mice have edematous corneas. Slc4a11 is expressed in the basolateral membrane of corneal endothelial cells; these cells normally promote fluid removal from the stroma by absorbing stromal osmolytes such as Na+, HCO3− (via the basolateral Na+/HCO3− cotransporter NBCe1) and lactate (via the basolateral H+/lactate cotransporter MCT1). The contribution of Slc4a11 to endothelial function is not fully understood. In a separate study in Xenopus oocytes, we have observed that mouse Slc4a11 mediates H+ conduction when extracellular pH is raised. At the basolateral membrane of corneal‐endothelial cells, Mct1‐mediated H+/lactate import would tend to raise surface pH (pHs) in the vicinity of Slc4a11. The near‐zero membrane potential reported for actively‐transporting corneal endothelia (Hodson and Wigham, J. Physiol., 1989), predicts that Slc4a11 should mediate H+ efflux in response to elevations in pHs. Thus we hypothesize that Mct1 action promotes Slc4a11‐mediated H+ efflux, which in turn supports Mct1 action and thereby the maintenance of corneal clarity. To investigate coupling between Mct1 and Slc4a11, we expressed Mct1 ± Slc4a11 in Xenopus oocytes. Under voltage clamp at 0 mV, we simultaneously monitored pHs and the Slc4a11‐dependent H+‐current as we applied lactate to the cells. Lactate application caused a sharp rise in pHs in all cells due to Mct action. In cells co‐expressing Mct1+Slc4a11, lactate application also caused a sustained increase in current due to Slc4a11‐mediated H+‐efflux (n=3), consistent with functional coupling between Mct1 and Slc4a11. Our preliminary data suggest that even in the absence of lactate, Slc4a11‐mediated H+‐conduction is significantly enhanced by Mct1 co‐expression (P=0.01, n=3), as if Mct1 also physically enhances the functional expression of Slc4a11. We performed two further assays to investigate the effect of Slc4a11 loss on H+ and lactate handling by mouse corneas. [1] We extracted tissue samples from the anterior section of wild‐type and Slc4a11‐null mouse eyes; Slc4a11‐null samples contained more lactate than wild‐type equivalents (P=0.02, n=4). [2] We measured corneal thickness in wild‐type and Slc4a11‐null mice by pachymetry. The application of acidic eye‐drops to the edematous corneas of Slc4a11‐null mice resulted in their de‐swelling (n=6, P<0.01). The thickness of de‐swollen corneas was not different from the thickness of wild‐type corneas. Together these data indicate that Slc4a11 plays an important role in support of Mct1 action, and thereby endothelial function.Support or Funding InformationSupported by Start‐up Funds from UB:SUNY (to MDP), an Unrestricted Grant from Research to Prevent Blindness (to SPP), and NIH R21‐EY021646 (to MLJ and MDP).