Loss of urotensin II receptor diminishes hyperglycemia and kidney injury in streptozotocin-treated mice

J Mol Endocrinol. 2022 Mar 25;68(3):167-178. doi: 10.1530/JME-21-0199. Print 2022 Apr 1.

Abstract

Beyond the CNS, urotensin II (UII) and its receptor (UT) are functionally expressed in peripheral tissues of the endocrine, cardiovascular, and renal systems. The expression levels of UII and UT in the kidney and circulating UII levels are increased in diabetes. UII also promotes mesangial proliferation and matrix accumulation in vitro. Here, we evaluate the effect of UT deletion on the development of hyperglycemia and diabetic kidney disease (DKD) in streptozotocin (STZ)-treated mice. Ten-week-old WT and UT knockout (KO) mice were injected with STZ for 5 days to induce diabetes. Blood glucose levels were measured weekly, and necropsy was performed 12 weeks after STZ injection. UT ablation slowed hyperglycemia and glucosuria in STZ-treated mice. UT KO also ameliorated STZ-induced increase in HbA1c, but not STZ-induced decrease in plasma insulin levels. However, STZ-induced increases in plasma glucagon concentration and immunohistochemical staining for glucagon in pancreatic islets were lessened in UT KO mice. UT ablation also protected against STZ-induced kidney derangements, including albuminuria, mesangial expansion, glomerular lesions, and glomerular endoplasmic reticulum stress. UT is expressed in a cultured pancreatic alpha cell line, and its activation by UII triggered membrane depolarization, T- and L-type voltage-gated Ca2+channel-dependent Ca2+influx, and glucagon secretion. These findings suggest that apart from direct action on the kidneys to cause injury, UT activation by UII may result in DKD by promoting hyperglycemia via induction of glucagon secretion by pancreatic alpha cells.

Keywords: alpha cells; diabetic kidney disease; glucagon; streptozotocin; urotensin II; urotensin II receptor.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Glucagon / metabolism
  • Hyperglycemia* / genetics
  • Hyperglycemia* / metabolism
  • Kidney / metabolism
  • Mice
  • Mice, Knockout
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Streptozocin / metabolism
  • Urotensins* / metabolism
  • Urotensins* / pharmacology

Substances

  • Receptors, G-Protein-Coupled
  • Urotensins
  • Streptozocin
  • Glucagon
  • urotensin II