Epithelia can adjust the permeability of the paracellular permeation route by regulating the degree of sealing of the tight junction. This is reflected by a transepithelial electrical resistance (TER) ranging from a few tenth to several thousands ohms X square centimeter, depending on the difference in composition between the fluid in the lumen and the interstitial fluid. Although teleologically sound, such correlation requires a physiological explanation. We have previously shown that urine extracts from different animal species increase the TER of MDCK monolayers, and that these effects are mediated by Epidermal Growth Factor (EGF) contained in the flowing intra-tubular fluid that eventually reaches the urine. This increase in TER is accompanied by an enhanced expression of claudin-4 (cln-4) and a decrement of cln-2. These changes are transient, peaking at ~16 h, and returning to control values in ~24 h. In the present work we investigated how EGF provokes this transient response, and found that the activation of extracellular-regulated kinases 1/2 (ERK1/2) by EGF is essential to increase TER and cln-4 content, but does not appear to participate in cln-2 down-regulation. On the other hand, prostaglandin synthesis stimulated by EGF, functions as a negative feedback turning off the signal initiated by EGF. Thus, PGE₂ blocks ERK1/2 by a mechanism that involves the G_s protein, adenylyl cyclase as well as protein kinase A (PKA) in MDCK cells. In summary: the permeability of a given segment of the nephron depends on the expression of different claudin types, which may be modulated by EGF and prostaglandins.