Podocytes of AT2 receptor knockout mice are protected from angiotensin II-mediated RAGE induction.

BACKGROUND/AIMS: The interaction of 'advanced glycation end products' (AGEs) and their receptor 'RAGE' plays an important role in diabetic nephropathy. We have previously found that in cultured differentiated podocytes, angiotensin II (ANG II) induces RAGE expression via an AT2 receptor-mediated pathway.

METHODS

To further confirm our results in an in vivo study, AT2 receptor knockout mice (AT2(-/-)) and wild-type mice were infused with ANG II by osmotic minipumps for 14 days.

RESULTS

As shown by immunohistochemistry, ANG II treatment of wild-type animals (C57BL6) allowed a significantly increased RAGE expression in renal podocytes in comparison to sham-operated C57BL6 mice. In contrast, RAGE expression in podocytes of ANG II-treated knockout mice (AT2(-/-)) was only moderately higher than in control animals, but significantly lower than in ANG II-treated wild-type mice. For the AGE species Nε-carboxymethyllysine, a similar immunohistochemical staining pattern was found. There was no significant change in glomerular AT1a receptor expression. However, no difference in RAGE mRNA expression could be found between ANG II-infused wild-type and AT2(-/-) animals by real-time PCR using whole kidney mRNA, presumably due to the low abundance of podocyte mRNA in these preparations. No effects were seen on glomerular apoptosis.

CONCLUSION

These data support the fact that ANG II-mediated RAGE induction in podocytes occurs via AT2 receptors. The present findings may suggest that not all ANG II-mediated changes in diabetic nephropathy can be treated with AT1 receptor blockers.