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P2Y2R contributes to the development of diabetic nephropathy by inhibiting autophagy response

Theodomir Dusabimana1, So Ra Kim2, Eun Jung Park2

  • 1Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 52727, Republic of Korea; Department of Convergence Medical Sciences, Institute of Health Sciences, Gyeongsang National University Graduate School, Jinju 52727, Republic of Korea.

Molecular Metabolism
|September 28, 2020
PubMed
Abstract

Insights

Mice lacking P2Y2R showed reduced kidney damage in diabetic nephropathy (DN). This protective effect was linked to improved autophagy, suggesting P2Y2R as a potential therapeutic target for DN.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Cellular Biology

Background:

  • Diabetic nephropathy (DN) is a major complication of diabetes, leading to end-stage renal disease.
  • Purinergic receptors, like P2Y2R, are implicated in kidney diseases, but their role in DN is unclear.
  • Autophagy dysregulation is observed in DN, suggesting its involvement in disease progression.

Purpose of the Study:

  • To investigate the role of P2Y2R in the pathogenesis of diabetic nephropathy (DN).
  • To determine if P2Y2R deficiency offers protection against DN by modulating autophagy.
  • To elucidate the underlying molecular mechanisms of P2Y2R's involvement in DN.

Main Methods:

  • A mouse model of DN was established using a high-fat diet and streptozotocin in wild-type and P2Y2R knockout mice.
  • Renal function was assessed via plasma parameters, and renal histology was examined.
  • Expression levels of autophagy regulatory proteins were analyzed.

Main Results:

  • P2Y2R knockout mice exhibited significantly reduced albuminuria, podocyte loss, glomerulopathy, tubular injury, apoptosis, and fibrosis in DN.
  • DN induced hyperglycemia and ATP release correlated with renal dysfunction in wild-type mice.
  • P2Y2R deficiency preserved renal function by inhibiting AKT-mediated FOXO3a phosphorylation, promoting autophagy gene transcription, decreasing ULK-1 phosphorylation, and activating Beclin-1 signaling.

Conclusions:

  • P2Y2R plays a detrimental role in diabetic nephropathy (DN) by impairing autophagy.
  • P2Y2R deficiency confers protection against DN through enhanced autophagy.
  • P2Y2R represents a potential therapeutic target for managing DN.
Keywords:
AutophagyDiabetic nephropathyFOXO3aGlomerulusKidneyP2Y2R

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