The effect of trehalose on autophagy-related proteins and cyst growth in a hypomorphic Pkd1 mouse model of autosomal dominant polycystic kidney disease

Cell Signal. 2020 Nov;75:109760. doi: 10.1016/j.cellsig.2020.109760. Epub 2020 Aug 29.

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder characterized by kidney cyst growth often resulting in end-stage renal disease. There is growing attention on understanding the role of impaired autophagy in ADPKD. Trehalose (TRE) has been shown to increase both protein stability and aggregate clearance and induce autophagy in neurodegenerative diseases. TRE treatment in wild type mice compared to vehicle resulted in increased expression in the kidney of Atg12-5 complex and increased Rab9a, autophagy-related proteins that play a role in the formation of autophagosomes. Thus, the aim of the study was to determine the effect of TRE on cyst growth and autophagy-related proteins, in the hypomorphic Pkd1RC/RC mouse model of ADPKD. Pkd1RC/RC mice were treated 2% TRE in water from days 50 to 120 of age. TRE did not slow cyst growth or improve kidney function or affect proliferation and apoptosis in Pkd1RC/RC kidneys. In Pkd1RC/RC vs. wild type kidneys, expression of the Atg12-5 complex was inhibited by TRE resulting in increased free Atg12 and TRE was unable to rescue the deficiency of the Atg12-5 complex. Rab9a was decreased in Pkd1RC/RC vs. wild type kidneys and unaffected by TRE. The TRE-induced increase in p62, a marker of autophagic cargo, that was seen in normal kidneys was blocked in Pkd1RC/RC kidneys. In summary, the autophagy phenotype in Pkd1RC/RC kidneys was characterized by decreases in crucial autophagy-related proteins (Atg12-5 complex, Atg5, Atg16L1), decreased Rab9a and increased mTORC1 (pS6S240/244, pmTORS2448) proteins. TRE increased Atg12-5 complex, Rab9a and p62 in normal kidneys, but was unable to rescue the deficiency in autophagy proteins or suppress mTORC1 in Pkd1RC/RC kidneys and did not protect against cyst growth.

Keywords: ADPKD; Apoptosis; Atg12; Atg5; PKD; Polycystic; Proliferation; Rab9a; TRE.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Autophagy / drug effects
  • Autophagy-Related Protein 12 / metabolism
  • Autophagy-Related Protein 5 / metabolism
  • Autophagy-Related Proteins
  • Mice
  • Mice, Inbred C57BL
  • Polycystic Kidney, Autosomal Dominant / drug therapy*
  • Protein Kinase C / metabolism*
  • Trehalose / pharmacology*
  • rab GTP-Binding Proteins / metabolism

Substances

  • Atg12 protein, mouse
  • Atg5 protein, mouse
  • Autophagy-Related Protein 12
  • Autophagy-Related Protein 5
  • Autophagy-Related Proteins
  • Trehalose
  • protein kinase D
  • Protein Kinase C
  • rab9 protein, mouse
  • rab GTP-Binding Proteins