TY - JOUR
T1 - Gene expression profiles of diabetic kidney disease and neuropathy in eNOS knockout mice
T2 - Predictors of pathology and RAS blockade effects
AU - Eid, Stephanie A.
AU - Hinder, Lucy M.
AU - Zhang, Hongyu
AU - Eksi, Ridvan
AU - Nair, Viji
AU - Eddy, Sean
AU - Eichinger, Felix
AU - Park, Meeyoung
AU - Saha, Jharna
AU - Berthier, Celine C.
AU - Jagadish, Hosagrahar V.
AU - Guan, Yuanfang
AU - Pennathur, Subramaniam
AU - Hur, Junguk
AU - Kretzler, Matthias
AU - Feldman, Eva L.
AU - Brosius, Frank C.
N1 - Publisher Copyright:
© 2021 Federation of American Societies for Experimental Biology
PY - 2021/5
Y1 - 2021/5
N2 - 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.
AB - 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.
KW - RAS blockade
KW - diabetic kidney disease
KW - diabetic peripheral neuropathy
KW - genome-wide expression
KW - self-organizing map
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U2 - 10.1096/fj.202002387R
DO - 10.1096/fj.202002387R
M3 - Article
C2 - 33788970
AN - SCOPUS:85103745195
SN - 0892-6638
VL - 35
JO - FASEB Journal
JF - FASEB Journal
IS - 5
M1 - e21467
ER -