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

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Item Type:	Article
Title:	The angiotensin II type 2 receptors protect renal tubule mitochondria in early stages of diabetes mellitus
Creators Name:	Micakovic, T., Papagiannarou, S., Clark, E., Kuzay, Y., Abramovic, K., Peters, J., Sticht, C., Volk, N., Fleming, T., Nawroth, P., Hammes, H.P., Alenina, N., Gröne, H.J. and Hoffmann, S.C.
Abstract:	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.
Keywords:	Angiotensin, Diabetic Nephropathy, Mitochondria, Oxidative Stress, Animals, Mice, Rats
Source:	Kidney International
ISSN:	0085-2538
Publisher:	Elsevier
Volume:	94
Number:	5
Page Range:	937-950
Date:	November 2018
Official Publication:	https://doi.org/10.1016/j.kint.2018.06.006
PubMed:	View item in PubMed

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