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Publication
Gene expression profiles of diabetic kidney disease and neuropathy in eNOS
knockout mice: Predictors of pathology and RAS blockade effects.
Authors Eid SA, Hinder LM, Zhang H, Eksi R, Nair V, Eddy S, Eichinger F, Park M, Saha J,
Berthier CC, Jagadish HV, Guan Y, Pennathur S, Hur J, Kretzler M, Feldman EL,
Brosius FC
Submitted By Submitted Externally on 12/3/2021
Status Published
Journal FASEB journal : official publication of the Federation of American Societies for Experimental Biology, REFERENCES
Year 2021
Date Published 5/1/2021
Volume : Pages 35 : e21467
PubMed Reference 33788970
Abstract Diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN) are two
common diabetic complications. However, their pathogenesis remains elusive and
current therapies are only modestly effective. We evaluated genome-wide
expression to identify pathways involved in DKD and DPN progression in db/db
eNOS-/- mice receiving renin-angiotensin-aldosterone system (RAS)-blocking drugs
to mimic the current standard of care for DKD patients. Diabetes and eNOS
deletion worsened DKD, which improved with RAS treatment. Diabetes also induced
DPN, which was not affected by eNOS deletion or RAS blockade. Given the multiple
factors affecting DKD and the graded differences in disease severity across
mouse groups, an automatic data analysis method, SOM, or self-organizing map was
used to elucidate glomerular transcriptional changes associated with DKD,
whereas pairwise bioinformatic analysis was used for DPN. These analyses
revealed that enhanced gene expression in several pro-inflammatory networks and
reduced expression of development genes correlated with worsening DKD. Although
RAS treatment ameliorated the nephropathy phenotype, it did not alter the more
abnormal gene expression changes in kidney. Moreover, RAS exacerbated expression
of genes related to inflammation and oxidant generation in peripheral nerves.
The graded increase in inflammatory gene expression and decrease in development
gene expression with DKD progression underline the potentially important role of
these pathways in DKD pathogenesis. Since RAS blockers worsened this gene
expression pattern in both DKD and DPN, it may partly explain the inadequate
therapeutic efficacy of such blockers.




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