Endogenous adenine mediates kidney injury in diabetic models and predicts diabetic kidney disease in patients
Kumar Sharma, … , Ravi Iyengar, for the Kidney Precision Medicine Project
Kumar Sharma, … , Ravi Iyengar, for the Kidney Precision Medicine Project
Published August 24, 2023
Citation Information: J Clin Invest. 2023;133(20):e170341. https://doi.org/10.1172/JCI170341.
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Research Article Nephrology

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

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.

Authors

Kumar Sharma, Guanshi Zhang, Jens Hansen, Petter Bjornstad, Hak Joo Lee, Rajasree Menon, Leila Hejazi, Jian-Jun Liu, Anthony Franzone, Helen C. Looker, Byeong Yeob Choi, Roman Fernandez, Manjeri A. Venkatachalam, Luxcia Kugathasan, Vikas S. Sridhar, Loki Natarajan, Jing Zhang, Varun S. Sharma, Brian Kwan, Sushrut S. Waikar, Jonathan Himmelfarb, Katherine R. Tuttle, Bryan Kestenbaum, Tobias Fuhrer, Harold I. Feldman, Ian H. de Boer, Fabio C. Tucci, John Sedor, Hiddo Lambers Heerspink, Jennifer Schaub, Edgar A. Otto, Jeffrey B. Hodgin, Matthias Kretzler, Christopher R. Anderton, Theodore Alexandrov, David Cherney, Su Chi Lim, Robert G. Nelson, Jonathan Gelfond, Ravi Iyengar, for the Kidney Precision Medicine Project

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Figure 5

Methylthioadenosine phosphorylase inhibitor ameliorates kidney injury in db/db mice with type 2 diabetes.

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Methylthioadenosine phosphorylase inhibitor ameliorates kidney injury in...
(A–C) Methylthio-DADMe-Immucillin-A (MTDIA) significantly reduced kidney (A) adenine levels, (B) kidney hypertrophy, (C) kidney KIM-1 levels, and (D) urine KIM-1 levels in diabetic mice. (E–G) MTDIA significantly reduced (E) diabetes-increased serum cystatin C and (F) partially reduced plasma creatinine and (G) albuminuria in diabetic mice. (H and I) Diabetes-induced kidney matrix protein levels were partially reduced by MTDIA. (J) Ribosomal S6 phosphorylation was partially reduced by MTDIA in the kidneys of db/db mice (n = 6 per group). *P < 0.05, **P < 0.01, ***P < 0.001, 2-tailed Student’s t test was used for 2 group comparisons. Data represent mean ± SD.