Endogenous adenine mediates kidney injury in diabetic models and predicts diabetic kidney disease in patients

Kidney Precision Medicine Project

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Diabetic kidney disease (DKD) can lead to end-stage kidney disease (ESKD) and mortality; however, few mechanistic biomarkers are available for high-risk patients, especially those without macroalbuminuria. Urine from participants with diabetes from the Chronic Renal Insufficiency Cohort (CRIC) study, the Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes (SMART2D), and the American Indian Study determined whether urine adenine/creatinine ratio (UAdCR) could be a mechanistic biomarker for ESKD. ESKD and mortality were associated with the highest UAdCR tertile in the CRIC study and SMART2D. ESKD was associated with the highest UAdCR tertile in patients without macroalbuminuria in the CRIC study, SMART2D, and the American Indian study. Empagliflozin lowered UAdCR in nonmacroalbuminuric participants. Spatial metabolomics localized adenine to kidney pathology, and single-cell transcriptomics identified ribonucleoprotein biogenesis as a top pathway in proximal tubules of patients without macroalbuminuria, implicating mTOR. Adenine stimulated matrix in tubular cells via mTOR and stimulated mTOR in mouse kidneys. A specific inhibitor of adenine production was found to reduce kidney hypertrophy and kidney injury in diabetic mice. We propose that endogenous adenine may be a causative factor in DKD.

Original languageEnglish (US)
JournalThe Journal of clinical investigation
Volume133
Issue number20
DOIs
StatePublished - Oct 16 2023

Keywords

  • Chronic kidney disease
  • Diabetes
  • Fibrosis
  • Nephrology

ASJC Scopus subject areas

  • General Medicine

Fingerprint

Dive into the research topics of 'Endogenous adenine mediates kidney injury in diabetic models and predicts diabetic kidney disease in patients'. Together they form a unique fingerprint.

Cite this