Although claudin-4 total knockout mice develop lethal hydronephrosis at one year of age33, principal cell-specific claudin-4 knockout leads to hypotension, hypochloremia and metabolic alkalosis caused by a severe renal wasting of chloride, without any alteration in claudin-8 abundance27, in agreement with our results (Fig. 6A). Here, CLDN4 is linked to hydronephrosis.