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

Kidney Int. 2018 Nov;94(5):937-950. doi: 10.1016/j.kint.2018.06.006. Epub 2018 Sep 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / biosynthesis
  • Animals
  • Cell Proliferation
  • Diabetes Mellitus, Experimental / complications*
  • Diabetic Nephropathies / prevention & control*
  • Gene Expression Profiling
  • Kidney Tubules / physiology*
  • Male
  • Mitochondria / chemistry
  • Mitochondria / physiology*
  • Rats
  • Reactive Oxygen Species / metabolism
  • Receptor, Angiotensin, Type 2 / analysis
  • Receptor, Angiotensin, Type 2 / physiology*
  • Streptozocin


  • Reactive Oxygen Species
  • Receptor, Angiotensin, Type 2
  • Streptozocin
  • Adenosine Triphosphate