TY - JOUR
T1 - Endogenous adenine mediates kidney injury in diabetic models and predicts diabetic kidney disease in patients
AU - for the Kidney Precision Medicine Project
AU - Sharma, Kumar
AU - Zhang, Guanshi
AU - Hansen, Jens
AU - Bjornstad, Petter
AU - Lee, Hak Joo
AU - Menon, Rajasree
AU - Hejazi, Leila
AU - Liu, Jian Jun
AU - Franzone, Anthony
AU - Looker, Helen C.
AU - Choi, Byeong Yeob
AU - Fernandez, Roman
AU - Venkatachalam, Manjeri A.
AU - Kugathasan, Luxcia
AU - Sridhar, Vikas S.
AU - Natarajan, Loki
AU - Zhang, Jing
AU - Sharma, Varun S.
AU - Kwan, Brian
AU - Waikar, Sushrut S.
AU - Himmelfarb, Jonathan
AU - Tuttle, Katherine R.
AU - Kestenbaum, Bryan
AU - Fuhrer, Tobias
AU - Feldman, Harold I.
AU - de Boer, Ian H.
AU - Tucci, Fabio C.
AU - Sedor, John
AU - Heerspink, Hiddo Lambers
AU - Schaub, Jennifer
AU - Otto, Edgar A.
AU - Hodgin, Jeffrey B.
AU - Kretzler, Matthias
AU - Anderton, Christopher R.
AU - Alexandrov, Theodore
AU - Cherney, David
AU - Lim, Su Chi
AU - Nelson, Robert G.
AU - Gelfond, Jonathan
AU - Iyengar, Ravi
N1 - Publisher Copyright:
© 2023, Sharma et al.
PY - 2023/10
Y1 - 2023/10
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI170341
DO - 10.1172/JCI170341
M3 - Article
C2 - 37616058
AN - SCOPUS:85174642552
SN - 0021-9738
VL - 133
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 20
M1 - e170341
ER -