Targeted gamma-secretase inhibition of Notch signaling activation in acute renal injury

Targeted gamma-secretase inhibition of
Notch signaling activation in acute renal injury. Am J Physiol Renal
Physiol 314: F736–F746, 2018. First published September 27, 2017;
doi:10.1152/ajprenal.00414.2016.—The Notch pathway has been reported to control tissue damage in acute kidney diseases. To investigate potential beneficial nephroprotective effects of targeting Notch,
we developed chemically functionalized -secretase inhibitors (GSIs)
targeting -glutamyltranspeptidase (gamma-GT) and/or -glutamylcyclotransferase (gamma-GCT), two enzymes overexpressed in the injured kidney, and evaluated them in in vivo murine models of acute tubular and
glomerular damage. Exposure of the animals to disease-inducing
drugs together with the functionalized GSIs improved proteinuria and,
to some extent, kidney dysfunction. The expression of genes involved
in the Notch pathway, acute inflammatory stress responses, and the
renin-angiotensin system was enhanced in injured kidneys, which
could be downregulated upon administration of functionalized GSIs.
Immunohistochemistry staining and Western blots demonstrated enhanced activation of Notch1 as detected by its cleaved active intra-
cellular domain during acute kidney injury, and this was downregulated by concomitant treatment with the functionalized GSIs. Thus
targeted gamma-secretase-based prodrugs developed as substrates for gamma-GT/
-GCT have the potential to selectively control Notch activation in
kidney diseases with subsequent regulation of the inflammatory stress
response and the renin-angiotensin pathways.