ATF4 in proximal tubules modulates kidney function and modifies the metabolome

Yuling Chi; Eduardo Mere Del Aguila; Tuo Zhang; Charles D Warren; Helen R Hoxie; Qiuying Chen; Steven S Gross; Jacob B Geri; David M Nanus; Lorraine J Gudas

doi:10.1007/s00109-025-02559-4

ATF4 in proximal tubules modulates kidney function and modifies the metabolome

J Mol Med (Berl). 2025 Jun 21. doi: 10.1007/s00109-025-02559-4. Online ahead of print.

Authors

Yuling Chi¹, Eduardo Mere Del Aguila¹, Tuo Zhang², Charles D Warren¹, Helen R Hoxie^{1

3}, Qiuying Chen¹, Steven S Gross¹, Jacob B Geri¹, David M Nanus⁴, Lorraine J Gudas^{5

6

7}

Affiliations

¹ Pharmacology Department, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065-4896, USA.
² The Genomics Core of Cornell University, 1300 York Ave, New York, NY, 10065, USA.
³ Weill Cornell Medicine and Weill Cornell Graduate School of Medical Sciences of Cornell University, 1300 York Ave, New York, NY, 10065, USA.
⁴ The Department of Medicine of Cornell University, 1300 York Ave, New York, NY, 10065, USA.
⁵ Pharmacology Department, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065-4896, USA. ljgudas@med.cornell.edu.
⁶ The Department of Medicine of Cornell University, 1300 York Ave, New York, NY, 10065, USA. ljgudas@med.cornell.edu.
⁷ Weill Cornell Medicine and Weill Cornell Graduate School of Medical Sciences of Cornell University, 1300 York Ave, New York, NY, 10065, USA. ljgudas@med.cornell.edu.

PMID: 40542844
DOI: 10.1007/s00109-025-02559-4

Abstract

Activating transcription factor 4 (ATF4) is a transcription factor that mediates the response to stress at the cellular, tissue, and organism level. We deleted the gene encoding ATF4 in the proximal tubules of the mouse kidney by using a temporal and cell type-specific approach. We show that ATF4 plays a major role in regulating the transcriptome and proteome, which, in turn, influences the metabolome and kidney functions. Genome-wide transcriptomics and single-plot, solid-phase-enhanced sample preparation (SP3)-proteomics studies reveal that ATF4 deletion changes more than 30% of transcripts and, similarly, corresponding proteins in the proximal tubules. Gene Set Enrichment Analysis indicates major changes in transporters, including amino acid transporters. Metabolomic analyses show that these changes in transporters are associated with altered profiles of amino acids in the blood, kidney, and urine. Stable isotope glutamine tracing in primary tubule cells isolated from kidney cortices confirms that ATF4 regulates glutamine transport and metabolism. We suggest that even in the absence of additional stresses, such as kidney injury, ATF4 in the proximal tubules modulates both retention of specific nutrients and excretion of catabolic products like creatinine to maintain normal kidney function. KEY MESSAGES: Activating transcription factor 4 (ATF4) deletion changed more than 30% of genome-wide transcripts and corresponding proteins in the proximal tubules. One set of the profound changes occurred in amino acid transporters and Slc22 family transporters. Changes in transporters were accompanied by altered profiles of amino acids and wastes in the blood, kidney, and urine. ATF4 in the kidney proximal tubules plays a key role in regulating both the reabsorption of nutrients and the excretion of wastes.

Keywords: Activating transcription factor 4 (ATF4); Kidney proximal tubules; Metabolomics; Proteomics; Transcriptomics; Transporters.

Abstract

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