Renin and kallikrein in connecting tubule of mouse.

BACKGROUND The observation of renin expression in connecting tubule, a segment that also expresses tissue kallikrein (KLK-1), raises two questions. Are the genes expressed in the same or in different cells of connecting tubule? Does this topography support the hypothesis that KLK-1 activates prorenin or is it more likely that it affords coordinated gene regulation? METHODS Renin and KLK-1 were examined by immunostaining and in situ hybridization. Renin activation by KLK-1 was investigated in vitro. In vivo, excretion of prorenin and active renin was compared in mice homozygous for targeted inactivation of KLK-1 (TK(-/-)) and normal littermates (TK(+/+)). RESULTS Using in situ immunostaining for renin and in situ hybridization for KLK-1 mRNA, we found that connecting tubule cells expressing renin also expressed KLK-1. We confirmed in vitro activation of prorenin by KLK-1, but found no difference in the ratio of active renin to prorenin in urine of TK(-/-) and TK(+/+) animals. Compared to TK(+/+) controls, TK(-/-) mice exhibited significantly lower 24-hour excretion of prorenin (5.05 +/- 1.16 mg Ang I/hour vs. 9.39 +/- 1.96 mg Ang I/hour, P < 0.05) and active renin (1.98 +/- 0.25 mg Ang I/hour vs. 3.58 +/- 0.39 mg Ang I/hour, P < 0.05), with no difference in either urine volumes or plasma renin concentrations. CONCLUSION Direct interaction between renin and KLK-1, not ruled out in vitro, is not supported in vivo. By contrast, lower excretion of active renin and prorenin in TK(-/-) compared to TK(+/+) suggest coordinated regulation of the two proteins in their participation to collecting duct function.