TY  - JOUR
AU  - Micakovic, Tamara
AU  - Papagiannarou, Stamatia
AU  - Clark, Euan
AU  - Kuzay, Yalcin
AU  - Abramovic, Katarina
AU  - Peters, Jörg
AU  - Sticht, Carsten
AU  - Volk, Nadine
AU  - Fleming, Thomas
AU  - Nawroth, Peter
AU  - Hammes, Hans-Peter
AU  - Alenina, Natalia
AU  - Gröne, Hermann-Josef
AU  - Hoffmann, Sigrid Christa
TI  - The angiotensin II type 2 receptors protect renal tubule mitochondria in early stages of diabetes mellitus.
JO  - Kidney international
VL  - 94
IS  - 5
SN  - 0085-2538
CY  - Basingstoke
PB  - Nature Publishing Group
M1  - DKFZ-2018-01453
SP  - 937-950
PY  - 2018
AB  - Diabetic nephropathy correlates more closely to defective mitochondria and increased oxidative stress in the kidney than to hyperglycemia. A key driving factor of diabetic nephropathy is angiotensin II acting via the G-protein-coupled cell membrane type 1 receptor. The present study aimed to investigate the role of the angiotensin II type 2 receptor (AT2R) at the early stages of diabetic nephropathy. Using receptor binding studies and immunohistochemistry we found that the mitochondria in renal tubules contain high-affinity AT2Rs. Increased renal mitochondrial AT2R density by transgenic overexpression was associated with reduced superoxide production of isolated mitochondria from non-diabetic rats. Streptozotocin-induced diabetes (28 days) caused a drop in the ATP/oxygen ratio and an increase in the superoxide production of isolated renal mitochondria from wild-type diabetic rats. This correlated with changes in the renal expression profile and increased tubular epithelial cell proliferation. AT2R overexpression in tubular epithelial cells inhibited all diabetes-induced renal changes including a drop in mitochondrial bioenergetics efficiency, a rise in mitochondrial superoxide production, metabolic reprogramming, and increased proliferation. Thus, AT2Rs translocate to mitochondria and can contribute to reno-protective effects at early stages of diabetes. Hence, targeted AT2R overexpression in renal cells may open new avenues to develop novel types of drugs preventing diabetic nephropathy.
LB  - PUB:(DE-HGF)16
C6  - pmid:30190172
DO  - DOI:10.1016/j.kint.2018.06.006
UR  - https://inrepo02.dkfz.de/record/137573
ER  -