Changes in acid-base balance lead to and require an adaptive increase in renal acid excretion that involves activation and regulation of various pathways in several nephron segments. However these adaptive changes are only partially understood. We used transcriptome profiling and SILAC based proteomics to identify genes and proteins regulated in the murine early and late proximal tubule in response to NH4Cl induced metabolic acidosis. Among the regulated proteins, we identified Gelsolin, involved in remodelling the actin cytoskeleton, as highly upregulated. Since gelsolin is abundantly expressed in kidney and has been shown to interact with H-ATPases and pyk2, two proteins important for acid-base homeostasis, we further characterized its role using Gelsolin KO mice subjected to acute (2 days) and chronic (7 days) metabolic acidosis.

Urinary calcium excretion and diuresis were increased in response to the NH4Cl challenge after 2 days in Gelsolin KO mice but no difference in acid-base homeostasis was detected. In kidney, mRNA levels of the Calcium Sensing Receptor were reduced, the calcium transport proteins TRPV5 and NCX were not altered. Aquaporin 3 mRNA but not AQP2 mRNA was lower. However after 7 days of NH4Cl challenge these differences were not observed anymore suggesting that gelsolin deletion might have only a transient effect on calcium and water homeostasis.

Figure 1