Attenuation of mTOR Signaling Is the Major Response Element in the Rescue Pathway of Chronic Kidney Disease in Rats

Wang, Jing; Chai, Lichao; Lu, Yi; Lu, Hua; Liu, Yanling; Zhang, Yingying

doi:10.1159/000505095

Cited by 8 publications

(7 citation statements)

References 39 publications

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“…Adenine exposure enhances tubular cell matrix production via the mTOR pathway and a prior study found that adenine is a potent stimulus for mTOR (17). Several published studies in mice and rats have also found that inhibiting mTOR protects against adenine-induced kidney disease (29)(30)(31). The mTOR pathway is likely relevant to human DKD as a recent study found stimulation of mTOR activity in kidney biopsies from patients with DKD (32) and our study with kidney biopsies from KPMP and CROCODILE demonstrate that a number of outputs of mTOR are elevated in DKD.…”

Section: Discussionmentioning

confidence: 94%

Role of endogenous adenine in kidney failure and mortality with diabetes

Sharma¹,

Zhang²,

Hansen

et al. 2023

Preprint

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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 Chronic Renal Insufficiency Cohort (CRIC), Singapore Study of Macro-Angiopathy and Reactivity in Type 2 Diabetes (SMART2D), and the Pima Indian Study determined if urine adenine/creatinine ratio (UAdCR) could be a mechanistic biomarker for ESKD. ESKD and mortality were associated with the highest UAdCR tertile in CRIC (HR 1.57, 1.18, 2.10) and SMART2D (HR 1.77, 1.00, 3.12). ESKD was associated with the highest UAdCR tertile in patients without macroalbuminuria in CRIC (HR 2.36, 1.26, 4.39), SMART2D (HR 2.39, 1.08, 5.29), and Pima Indian study (HR 4.57, CI 1.37-13.34). Empagliflozin lowered UAdCR in non-macroalbuminuric participants. Spatial metabolomics localized adenine to kidney pathology and transcriptomics identified ribonucleoprotein biogenesis as a top pathway in proximal tubules of patients without macroalbuminuria, implicating mammalian target of rapamycin (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.

show abstract

Section: Discussionmentioning

confidence: 94%

Role of endogenous adenine in kidney failure and mortality with diabetes

Sharma¹,

Zhang²,

Hansen

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Adenine exposure enhances tubular cell matrix production via the mTOR pathway, and a prior study found that adenine is a potent stimulus for mTOR ( 17 ). Several published studies in mice and rats have also found that inhibiting mTOR protects against adenine-induced kidney disease ( 28 – 30 ). The mTOR pathway is likely relevant to human DKD, as a recent study found stimulation of mTOR activity in kidney biopsies from patients with DKD ( 31 ) and our study with kidney biopsies from KPMP and CROCODILE demonstrated that a number of outputs of mTOR are elevated in DKD.…”

Section: Discussionmentioning

confidence: 99%

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

Sharma,

Zhang,

Hansen

et al. 2023

Journal of Clinical Investigation

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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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“…55 Furthermore, EIF2 and mTOR pathways are also known to play a role in both autophagy and fibrosis, making them ideal therapeutic targets for the prevention of COVID-associated AKI progression or PASC. 42,56 These instances of cardiorenal crosstalk play a common role in COVID-19 AKI and drive the progression to CKD in the long-term. 57…”

Section: Discussionmentioning

confidence: 99%

Peripheral Transcriptomics in Acute and Long-Term Kidney Dysfunction in SARS-CoV2 Infection

Jayaraman,

Rajagopal,

Paranjpe

et al. 2023

Preprint

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Background. Acute kidney injury (AKI) is common in hospitalized patients with SARS-CoV2 infection despite vaccination and leads to long-term kidney dysfunction. However, peripheral blood molecular signatures in AKI from COVID-19 and their association with long-term kidney dysfunction are yet unexplored. Methods. In patients hospitalized with SARS-CoV2, we performed bulk RNA sequencing using peripheral blood mononuclear cells (PBMCs). We applied linear models accounting for technical and biological variability on RNA-Seq data accounting for false discovery rate (FDR) and compared the functional enrichment and pathway results to a historical sepsis-AKI cohort. Finally, we evaluated the association of these signatures with long-term trends in kidney function. Results. Of 283 patients, 106 had AKI. After adjustment for sex, age, mechanical ventilation, and chronic kidney disease (CKD), we identified 2635 significant differential gene expressions at FDR<0.05. Top canonical pathways were EIF2 signaling, oxidative phosphorylation, mTOR signaling, and Th17 signaling, indicating mitochondrial dysfunction and endoplasmic reticulum (ER) stress. Comparison with sepsis associated AKI showed considerable overlap of key pathways (48.14%). Using follow-up estimated glomerular filtration rate (eGFR) measurements from 115 patients, we found that 164/2635 (6.2%) of the significantly differentiated genes were associated with overall decrease in long-term kidney function. The strongest associations were autophagy, renal impairment via fibrosis and cardiac structure/function. Conclusions. We show that AKI in SARS-CoV2 is a multifactorial process with mitochondrial dysfunction driven by ER stress whereas long-term kidney function decline is associated with cardiac structure and function, and immune dysregulation. Functional overlap with sepsis-AKI also highlights common signatures indicating generalizability in therapeutic approaches.

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Attenuation of mTOR Signaling Is the Major Response Element in the Rescue Pathway of Chronic Kidney Disease in Rats

Cited by 8 publications

References 39 publications

Role of endogenous adenine in kidney failure and mortality with diabetes

Role of endogenous adenine in kidney failure and mortality with diabetes

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

Peripheral Transcriptomics in Acute and Long-Term Kidney Dysfunction in SARS-CoV2 Infection

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