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Renin and kallikrein in connecting tubule of mouse
Andreas Rohrwasser1, Tomoaki Ishigami, Barbu Gociman
1Department of Human Genetics, University of Utah, Health Sciences Center, Salt Lake City, Utah 84112, USA.
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.
Insights
Tissue kallikrein (KLK-1) and renin are co-expressed in the connecting tubule. KLK-1 inactivation in mice reduced renin and prorenin excretion, suggesting coordinated gene regulation rather than direct activation.
Area of Science:
- Nephrology
- Molecular Biology
- Biochemistry
Background:
- Renin and tissue kallikrein (KLK-1) are expressed in the connecting tubule.
- Investigating whether these genes are in the same or different cells and their functional relationship.
Purpose of the Study:
- To determine the cellular localization of renin and KLK-1 in the connecting tubule.
- To investigate the functional interaction between KLK-1 and renin in vivo and in vitro.
Main Methods:
- Immunostaining and in situ hybridization for renin and KLK-1.
- In vitro prorenin activation assays.
- Comparison of urinary prorenin and active renin excretion in KLK-1 knockout mice (TK(-/-)) and wild-type littermates (TK(+/+)).
Main Results:
- Renin and KLK-1 were found to be co-expressed in the same connecting tubule cells.
- KLK-1 activated prorenin in vitro.
- TK(-/-) mice showed significantly lower 24-hour excretion of both prorenin and active renin compared to TK(+/+) mice.
Conclusions:
- Direct in vivo interaction between renin and KLK-1 is not supported.
- Lower excretion of renin and prorenin in TK(-/-) mice suggests coordinated regulation of these proteins in collecting duct function.
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