Kevin A Lidberg1, Selvaraj Muthusamy2, Mohamed Adil2, Anish Mahadeo1, Jade Yang1, Ranita S Patel3, Lu Wang4, Theo K Bammler4, Jonathan Reichel2, Catherine K Yeung5,6, Jonathan Himmelfarb6,7, Edward J Kelly8,6, Shreeram Akilesh9,6. 1. Department of Pharmaceutics, University of Washington, Seattle, Washington. 2. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington. 3. Seattle Children's Hospital, Seattle, Washington. 4. Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington. 5. Department of Pharmacy, University of Washington, Seattle, Washington. 6. Kidney Research Institute, Seattle, Washington. 7. Nephrology Division, Department of Medicine, University of Washington, Seattle, Washington. 8. Department of Pharmaceutics, University of Washington, Seattle, Washington EdKelly@uw.edu Shreeram@uw.edu. 9. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington EdKelly@uw.edu Shreeram@uw.edu.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Our results demonstrate a causal role for serum proteins in tubular injury and identify regulatory mechanisms and novel pathways for intervention.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Our results demonstrate a causal role for serum proteins in tubular injury and identify regulatory mechanisms and novel pathways for intervention.
Authors: Shiv Pratap S Yadav; Ruben M Sandoval; Jingfu Zhao; Yifan Huang; Exing Wang; Sudhanshu Kumar; Silvia B Campos-Bilderback; George Rhodes; Yehia Mechref; Bruce A Molitoris; Mark C Wagner Journal: Am J Physiol Renal Physiol Date: 2020-12-07