Klotho regulation by albuminuria is dependent on ATF3 and endoplasmic reticulum stress

Area of Science:

• Nephrology
• Molecular Biology
• Biochemistry

Background:

• Proteinuria is a significant marker for declining kidney function and increased cardiovascular risk.
• The precise mechanisms linking albuminuria to altered Klotho expression, a key protein in aging and kidney health, remain largely unknown.

Purpose of the Study:

• To elucidate the molecular mechanisms by which albuminuria affects Klotho expression in proteinuric kidney disease.
• To investigate the role of endoplasmic reticulum (ER) stress in mediating albuminuria-induced Klotho downregulation.

Main Methods:

• Utilized the POD-ATTAC mouse model and kidney epithelial cell lines to study Klotho expression in the presence of albumin.
• Assessed Klotho transcription, protein half-life, and the impact of ER stress modulators (e.g., 4-PBA).
• Investigated the role of ATF3 and ATF4 transcription factors in regulating Klotho expression via promoter binding.

Main Results:

• Albumin significantly decreased Klotho expression in both mouse models and cell lines.
• Downregulation involved reduced Klotho transcription and accelerated protein degradation, independent of ADAM protease cleavage.
• Albumin induced ER stress and ATF3/ATF4 activation, which directly suppressed Klotho transcription.
• Inhibition of ER stress partially restored Klotho protein levels by reducing degradation.

Conclusions:

• Albuminuria diminishes Klotho expression through ER stress-induced transcriptional repression and enhanced protein degradation.
• Modulating ER stress presents a potential therapeutic strategy to counteract Klotho loss in proteinuric kidney diseases.
• These findings offer insights into the pathogenesis of renal and cardiovascular complications associated with proteinuria.