In kidney, the expression of the chloride/anion exchanger pendrin (SLC26A4) is restricted to the apical side of non-type A intercalated cells in the connecting segment and cortical collecting duct, that are activated during metabolic alkalosis. It has been shown that pendrin abundance is reduced during metabolic acidosis induced by oral NH4Cl-loading. It has been also demonstrated that pendrin abundance is decreased upon chloride loading. Thus, it is unclear if the decrease in pendrin expression seen during NH4Cl induced acidosis is due the chloride load or occurs also independently during acidosis. Therefore we investigated pendrin regulation under different conditions. Pendrin expression was reduced under NaCl, NH4Cl, and (NH4)2SO4 loading. Low urinary chloride excretion stimulated pendrin expression. However, metabolic acidosis caused by acetazolamide or (NH4)2SO4-loading prevented the increase or even reduced pendrin expression despite low urinary chloride excretion. Thus, pendrin expression is primarily regulated by urinary chloride-excretion but can also be reduced during severe metabolic acidosis despite low urinary chloride-excretion.