Pathogenesis of diabesity-induced kidney disease: role of kidney nutrient sensing

Liad Hinden, Aviram Kogot-Levin, Joseph Tam*, Gil Leibowitz

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

11 Scopus citations

Abstract

Diabetes kidney disease (DKD) is a major healthcare problem associated with increased risk for developing end-stage kidney disease and high mortality. It is widely accepted that DKD is primarily a glomerular disease. Recent findings however suggest that kidney proximal tubule cells (KPTCs) may play a central role in the pathophysiology of DKD. In diabetes and obesity, KPTCs are exposed to nutrient overload, including glucose, free-fatty acids and amino acids, which dysregulate nutrient and energy sensing by mechanistic target of rapamycin complex 1 and AMP-activated protein kinase, with subsequent induction of tubular injury, inflammation, and fibrosis. Pharmacological treatments that modulate nutrient sensing and signaling in KPTCs, including cannabinoid-1 receptor antagonists and sodium glucose transporter 2 inhibitors, exert robust kidney protective effects. Shedding light on how nutrients are sensed and metabolized in KPTCs and in other kidney domains, and on their effects on signal transduction pathways that mediate kidney injury, is important for understanding the pathophysiology of DKD and for the development of novel therapeutic approaches in DKD and probably also in other forms of kidney disease.

Original languageAmerican English
Pages (from-to)901-921
Number of pages21
JournalFEBS Journal
Volume289
Issue number4
DOIs
StatePublished - Feb 2022

Bibliographical note

Funding Information:
This work was partially supported by Israel Science Foundation (#398/20) and Israel Science Foundation-JFRFI (#2982/20) grants to GL, and ERC-2015-StG (#676841) and Israel Science Foundation (#158/18) grants to JT.

Publisher Copyright:
© 2021 Federation of European Biochemical Societies.

Keywords

  • AMPK
  • CBR
  • SGLT2
  • diabetes
  • mTORC1
  • obesity
  • Humans
  • Nutrients/metabolism
  • Diabetic Nephropathies/metabolism

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