ATF4 in proximal tubules modulates kidney function and modifies the metabolome

Area of Science:

• Nephrology
• Molecular Biology
• Biochemistry

Background:

• Activating transcription factor 4 (ATF4) is a key stress-response transcription factor.
• Its role in normal kidney function, independent of external stress, is not fully understood.

Purpose of the Study:

• To investigate the role of ATF4 in mouse kidney proximal tubules under normal physiological conditions.
• To determine the impact of ATF4 deletion on kidney transcriptome, proteome, metabolome, and function.

Main Methods:

• Temporal and cell type-specific deletion of the ATF4 gene in mouse kidney proximal tubules.
• Genome-wide transcriptomics and proteomics (SP3).
• Metabolomic analyses and stable isotope glutamine tracing in primary tubule cells.

Main Results:

• ATF4 deletion altered over 30% of transcripts and proteins in proximal tubules.
• Significant changes observed in amino acid transporters and Slc22 family transporters.
• Altered amino acid profiles and waste products (e.g., creatinine) in blood, kidney, and urine.

Conclusions:

• ATF4 is crucial for regulating nutrient reabsorption and waste excretion in kidney proximal tubules.
• ATF4 modulates kidney function by influencing transporter expression and metabolism, even in the absence of stress.
• These findings highlight ATF4's role in maintaining kidney homeostasis.