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The angiotensin II type 2 receptors protect renal tubule mitochondria in early stages of diabetes mellitus

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 investi...

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Main Authors: Micakovic, Tamara (Author) , Papagiannarou, Stamatia (Author) , Clark, Euan (Author) , Kuzay, Yalçın (Author) , Abramovic, Katarina (Author) , Peters, Jörg (Author) , Sticht, Carsten (Author) , Volk, Nadine (Author) , Fleming, Thomas (Author) , Nawroth, Peter Paul (Author) , Hammes, Hans-Peter (Author) , Alenina, Natalia (Author) , Gröne, Hermann-Josef (Author) , Hoffmann, Sigrid (Author)
Format: Article (Journal)
Language:English
Published: 4 September 2018
In: Kidney international
Year: 2018, Volume: 94, Issue: 5, Pages: 937-950
ISSN:1523-1755
DOI:10.1016/j.kint.2018.06.006
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.kint.2018.06.006
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Author Notes:Tamara Micakovic, Stamatia Papagiannarou, Euan Clark, Yalcin Kuzay, Katarina Abramovic, Jörg Peters, Carsten Sticht, Nadine Volk, Thomas Fleming, Peter Nawroth, Hans-Peter Hammes, Natalia Alenina, Hermann-Josef Gröne and Sigrid Christa Hoffmann
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Summary: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.
Item Description:Gesehen am 14.04.2020
Physical Description:Online Resource
ISSN:1523-1755
DOI:10.1016/j.kint.2018.06.006

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