Serum Protein Exposure Activates a Core Regulatory Program Driving Human Proximal Tubule Injury

• Published in: Journal of the American Society of Nephrology Vol. 33; no. 5; pp. 949 - 965
• Main Authors: Lidberg, Kevin A, Muthusamy, Selvaraj, Adil, Mohamed, Mahadeo, Anish, Yang, Jade, Patel, Ranita S, Wang, Lu, Bammler, Theo K, Reichel, Jonathan, Yeung, Catherine K, Himmelfarb, Jonathan, Kelly, Edward J, Akilesh, Shreeram
• Format: Journal Article
• Language: English
• Published: United States American Society of Nephrology 01.05.2022
• Subjects: Animals; Basic Research; Blood Proteins; Female; Humans; Kidney Diseases - metabolism; Kidney Tubules - metabolism; Kidney Tubules, Proximal - metabolism; Male; Proteinuria - metabolism; albuminuria; transcription regulation; gene transcription; acute renal failure; blood proteins; proteinuria; proximal tubule; renal tubular epithelial cells; gene expression; nephrotic syndrome
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2021060751

The kidneys efficiently filter waste products while retaining serum proteins in the circulation. However, numerous diseases compromise this barrier function, resulting in spillage of serum proteins into the urine (proteinuria). Some studies of glomerular filtration suggest that tubules may be physiologically exposed to nephrotic-range protein levels. Therefore, whether serum components can directly injure the downstream tubular portions of the kidney, which in turn can lead to inflammation and fibrosis, remains controversial. We tested the effects of serum protein exposure in human kidney tubule microphysiologic systems and with orthogonal epigenomic approaches since animal models cannot directly assess the effect of serum components on tubules. Serum, but not its major protein component albumin, induced tubular injury and secretion of proinflammatory cytokines. Epigenomic comparison of serum-injured tubules and intact kidney tissue revealed canonical stress-inducible regulation of injury-induced genes. Concordant transcriptional changes in microdissected tubulointerstitium were also observed in an independent cohort of patients with proteinuric kidney disease. Our results demonstrate a causal role for serum proteins in tubular injury and identify regulatory mechanisms and novel pathways for intervention.