Summary
The glomerulus has been at the center of attention as the primary site of injury in
diabetic nephropathy (DN). Although there is no question that there are changes seen
in the glomerulus, it is also well known that tubulointerstitial changes are a prominent
component of the disease, especially in patients with type 2 diabetes. The level of
albuminuria and DN disease progression best correlate with tubular degeneration and
interstitial fibrosis. Nephrotoxicity studies in animals reveal that albuminuria is
a highly sensitive marker of early tubular toxicity even in the absence of glomerular
pathology. Urinary biomarker data in human beings support the view that proximal tubule
injury contributes in a primary way, rather than in a secondary manner, to the development
of early DN. I present a model in which very specific injury to the proximal tubule
in vivo in the mouse results in severe inflammation, loss of blood vessels, interstitial
fibrosis, and glomerulosclerosis. Increased glucose levels, free glycation adducts,
reactive oxygen species, and oxidized lipids result in toxicity to tubule epithelia.
This results in loss of cells with a stimulus to repair the epithelium. However, because
of sublethal injury there is cell-cycle arrest in epithelial cells attempting to replace
damaged cells. This leads to epithelial secretion of both profibrogenic growth factors,
collagens, and factors that cause pericytes to proliferate and differentiate into
myofibroblasts, leading to endothelial destabilization and capillary rarefaction.
Local ischemia ensues with further injury to the tubules, more profibrogenic mediators,
matrix protein deposition, fibrosis, and glomerulosclerosis.
Keywords
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Article info
Footnotes
Financial support: Supported by National Institutes of Health grants DK39773, DK72381, and DK054741.
Conflict of interest statement: The author is a co-inventor on kidney injury molecule-1 patents that are assigned to Partners Healthcare and licensed by Partners Healthcare to Johnson and Johnson, Sekisui, BiogenIdec, and a number of research reagent companies. The author also is a consultant for Sekisui.
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© 2012 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
