Abstract
Proteinuria is a prognostic indicator of progressive kidney disease and poor cardiovascular outcomes. Abnormally filtered bioactive macromolecules interact with proximal tubular epithelial cells (PTECs), which results in the development of proteinuric nephropathy. This condition is characterized by alterations in PTEC growth, apoptosis, gene transcription and inflammatory cytokine production as a consequence of dysregulated signaling pathways that are stimulated by proteinuric tubular fluid. The megalin–cubilin complex mediates the uptake of several proteins, including albumin, into PTECs. Megalin might also possess intrinsic signaling properties and the ability to regulate cell signaling pathways and gene transcription after processing regulated intramembrane proteolysis. Megalin could, therefore, link abnormal PTEC albumin exposure with altered growth factor receptor activation, proinflammatory and profibrotic signaling, and gene transcription. Evidence now suggests that other PTEC pathways for protein reabsorption of (patho)physiological importance might be mediated by the neonatal Fc receptor and CD36.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Baines, R. J. & Brunskill, N. J. The molecular interactions between filtered proteins and proximal tubular cells in proteinuria. Nephron Exp. Nephrol. 110, 67–71 (2008).
Brunskill, N. J. Albumin signals the age of proteinuric nephropathy. J. Am. Soc. Nephrol. 15, 504–505 (2004).
Christensen, E. I., Verroust, P. J. & Nielsen, R. Receptor-mediated endocytosis in renal proximal tubule. Pflugers Arch. 485, 1039–1048 (2009).
Willnow, T. E. et al. Defective forebrain development in mice lacking gp330/megalin. Proc. Natl Acad. Sci. USA 93, 8460–8464 (1996).
Leheste, J. R. et al. Hypocalcaemia and osteopathy in mice with kidney-specific megalin gene defect. FASEB J. 17, 247–249 (2003).
Lillis, A. P., Van Duyn, L. B., Murphy-Ullrich, J. E. & Strickland, D. K. LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies. Physiol. Rev. 88, 887–918 (2008).
Yuseff, M. I., Farfan, P., Bu, G. & Marzolo, M. P. A cytoplasmic PPPSP motif determines megalin's phosphorylation and regulates receptor's recycling and surface expression. Traffic 8, 1215–1230 (2007).
Biemesderfer, D. Regulated intramembrane proteolysis of megalin: linking urinary protein and gene regulation in proximal tubule? Kidney Int. 69, 1717–1721 (2006).
Li, Y., Cong, R. & Biemesderfer, D. The COOH terminus of megalin regulates gene expression in opossum kidney proximal tubular cells. Am. J. Physiol. Cell Physiol. 295, C529–C537 (2008).
Thrailkill, K. M. et al. Microalbuminuria in type 1 diabetes mellitus is associated with enhanced excretion of the endocytic, multiligand receptor megalin and cubilin. Diabetes Care 32, 1266–1268 (2009).
Terzi, F. et al. Targeted expression of a dominant-negative EGF-R in the kidney reduces tubule-interstitial lesions after renal injury. J. Clin. Invest. 106, 225–234 (2000).
Reich, H. et al. Albumin activates ERK via EGF receptor in human renal epithelial cells. J. Am. Soc. Nephrol. 16, 1266–1278 (2005).
Gesualdo, L. et al. Expression of epidermal growth factor and its receptor in normal and diseased human kidney: an immunohistochemical and in situ hybridization study. Kidney Int. 49, 656–665 (1996).
Shi, Y., Mantuano, E., Inoue, G., Campana, W. M. & Gonias, S. L. Ligand binding to LRP1 transactivates Trk receptors by a Src family kinase-dependent pathway. Sci. Signal. 2, ra18 (2009).
Caruso-Neves, C. et al. PKB and megalin determine the survival or death of renal proximal tubule cells. Proc. Natl Acad. Sci. USA 103, 18810–18815 (2006).
Takase, O. et al. Inhibition of NF-κB-dependent Bcl-xL expression by clusterin promotes albumin-induced tubular cell apoptosis. Kidney Int. 73, 567–577 (2008).
Theilig, F. et al. Abrogation of protein uptake through megalin-deficient proximal tubules does not safeguard against tubulointerstitial injury. J. Am. Soc. Nephrol. 18, 1824–1834 (2007).
Motoyoshi, Y. et al. Megalin contributes to the early injury of proximal tubular cells during nonselective proteinuria. Kidney Int. 74, 1262–1269 (2008).
Roopenian, D. C. & Akilesh, S. FcRn: the neonatal Fc receptor comes of age. Nat. Rev. Immunol. 7, 715–725 (2007).
Haymann, J. P. et al. Characterization and localization of the neonatal Fc receptor in adult human kidney. J. Am. Soc. Nephrol. 11, 632–639 (2000).
Sarav, M. et al. Renal FcRn reclaims albumin but facilitates elimination of IgG. J. Am. Soc. Nephrol. 20, 1941–1952 (2009).
Febbraio, M. et al. A null mutation in murine CD36 reveals an important role in fatty acid and lipoprotein metabolism. J. Biol. Chem. 274, 19055–19062 (1999).
Susztak, K., Ciccone, E., McCue, P., Sharma, K. & Böttinger, E. P. Multiple metabolic hits converge on CD36 as novel mediator of tubular epithelial apoptosis in diabetic nephropathy. PLoS Med. 2, e45 (2005).
Iwao, Y. et al. CD36 is one of important receptors promoting renal tubular injury by advanced glycation end products. Am. J. Physiol. Renal Physiol. 295, F1871–F1880 (2008).
Okamura, D. M., López-Guisa, J., Koelsch, K., Collins, S. & Eddy, A. A. Atherogenic scavenger receptor modulation in the tubulointerstitium in response to chronic renal injury. Am. J. Physiol. Renal Physiol. 293, F575–F585 (2007).
Yang, Y.-L. et al. CD36 is a novel and potential anti-fibrogenic target in albumin-induced renal proximal tubule fibrosis. J. Cell. Biochem. 101, 735–744 (2007).
Okamura, D. M. et al. CD36 regulates oxidative stress and inflammation in hypercholesterolemic CKD. J. Am. Soc. Nephrol. 20, 495–505 (2009).
Author information
Authors and Affiliations
Contributions
R. J. Baines and N. J. Brunskill contributed equally to researching data for the article, discussing content, writing and reviewing/editing the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Baines, R., Brunskill, N. Tubular toxicity of proteinuria. Nat Rev Nephrol 7, 177–180 (2011). https://doi.org/10.1038/nrneph.2010.174
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrneph.2010.174
This article is cited by
-
Nephrotic syndrome: pathophysiology and consequences
Journal of Nephrology (2023)
-
Analysis of the ratio of urinary beta-2-microglobulin to total protein concentration in children with isolated tubulointerstitial disease
Clinical and Experimental Nephrology (2023)
-
Novel pathogenic variants in CUBN uncouple proteinuria from renal function
Journal of Translational Medicine (2022)
-
Mono-macrophage-Derived MANF Protects Against Lipopolysaccharide-Induced Acute Kidney Injury via Inhibiting Inflammation and Renal M1 Macrophages
Inflammation (2021)
-
Development and validation of hybrid Brillouin-Raman spectroscopy for non-contact assessment of mechano-chemical properties of urine proteins as biomarkers of kidney diseases
BMC Nephrology (2020)