Diabetologie und Stoffwechsel 2016; 11 - P146
DOI: 10.1055/s-0036-1580893

Angiotensin II type 2 receptor (AT2R) localizes to mitochondria of renal tubules and modifies mitochondrial function in early stages of type 1 diabetes in rats

T Micakovic 1, M Papagiannarou 1, E Clark 1, N Volk 2, T Fleming 2, HJ Gröne 3, S Hoffmann 1
  • 1Medical Faculty Mannheim, University of Heidelberg, Medical Research Center, Mannheim, Germany
  • 2Medical Faculty Heidelberg, University of Heidelberg, Heidelberg, Germany
  • 3DKFZ, Heidelberg, Germany

Background: Diabetic nephropathy (DN) is associated with mitochondrial dysfunction and increased activity of the local Renin-Angiotensin-System.

Aim: This study aimed to verify the existence of mitochondrial AT2Rs and their role in DN.

Methods: AT2Rs on mitochondria were demonstrated by immunohistochemistry using kidney sections of AT2R overexpressing transgenic rats (TGR) and AT2R-knockout mice and by receptor binding studies on isolated mitochondria. Mitochondrial functions (oxygen consumption, ATP-, superoxide- and H2O2-production) were evaluated in isolated mitochondria from TGR and respective wildtyp controls (WT), which were subjected either to STZ-diabetes for 28 days or to continuous Ang II infusion for 12 days.

Results: TGR revealed a 30-fold increase in AT2R density in renal tubules vs. WT. In pure mitochondrial fractions from TGR kidneys Bmax for AT2R was 1500 fmol/mg protein. This constitutes 63% of the Bmax for AT2R measured in the TGR plasma membrane fraction. The estimates for ligand binding affinity KD in the mitochondrial and plasma membrane fraction were comparable (395 pM and 300 pM, respectively). Immunohistochemistry revealed co-localization of AT2R with mitochondrial markers. Ang II infusion decreased mitochondrial activity as indicated by lower oxygen consumption as well as ATP and superoxide production in WT but not in TGR. In early stages of type 1 diabetes (28 days) however, the oxygen consumption and superoxide production were significantly increased in WT. This increase was blocked in TGR.

Conclusion: AT2Rs locate to mitochondria in renal tubules and seems to preserve mitochondrial function in stressed conditions like increased Ang II activity and early STZ- diabetes.