Tissue kallikrein (TK) is a serine protease synthetized in renal tubular cells located upstream from the collecting duct where renal potassium balance is regulated. Because secretion of TK is promoted by K
+
intake, we hypothesized that this enzyme might regulate plasma K
+
concentration ([K
+
]). We showed in wild-type mice that renal K
+
and TK excretion increase in parallel after a single meal, representing an acute K
+
load, whereas aldosterone secretion is not modified. Using aldosterone synthase-deficient mice, we confirmed that the control of TK secretion is aldosterone-independent. Mice with
TK
gene disruption (
TK
â/â
) were used to assess the impact of the enzyme on plasma [K
+
]. A single large feeding did not lead to any significant change in plasma [K
+
] in
TK
+/+
, whereas
TK
â/â
mice became hyperkalemic. We next examined the impact of
TK
disruption on K
+
transport in isolated cortical collecting ducts (CCDs) microperfused in vitro. We found that CCDs isolated from
TK
â/â
mice exhibit net transepithelial K
+
absorption because of abnormal activation of the colonic H
+
,K
+
-ATPase in the intercalated cells. Finally, in CCDs isolated from
TK
â/â
mice and microperfused in vitro, the addition of TK to the perfusate but not to the peritubular bath caused a 70% inhibition of H
+
,K
+
-ATPase activity. In conclusion, we have identified the serine protease TK as a unique kalliuretic factor that protects against hyperkalemia after a dietary K
+
load.