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NOX4-dependent regulation of ENaC in hypertension and diabetic kidney disease. FASEB J 2020 Oct;34(10):13396-13408



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Pubmed Central ID




Scopus ID

2-s2.0-85089380202 (requires institutional sign-in at Scopus site)   16 Citations


NADPH oxidase 4 (NOX4) is the most abundant NOX isoform in the kidney; however, its importance for renal function has only recently emerged. The NOX4-dependent pathway regulates many factors essential for proper sodium handling in the distal nephron. However, the functional significance of this pathway in the control of sodium reabsorption during the initiation of chronic kidney disease is not established. The goal of this study was to test Nox4-dependent ENaC regulation in two models: SS hypertension and STZ-induced type 1 diabetes. First, we showed that genetic ablation of Nox4 in Dahl salt-sensitive (SS) rat attenuated a high-salt (HS)-induced increase in epithelial Na+ channel (ENaC) activity in the cortical collecting duct. We also found that H2 O2 upregulated ENaC activity, and H2 O2 production was reduced in both the renal cortex and medulla in SSNox4-/- rats fed an HS diet. Second, in the streptozotocin model of hyperglycemia-induced renal injury ENaC activity in hyperglycemic animals was elevated in SS but not SSNox4-/- rats. NaCl cotransporter (NCC) expression was increased compared to healthy controls, while expression values between SS and SSNox4-/- groups were similar. These data emphasize a critical contribution of the NOX4-mediated pathway in maladaptive upregulation of ENaC-mediated sodium reabsorption in the distal nephron in the conditions of HS- and hyperglycemia-induced kidney injury.

Author List

Pavlov TS, Palygin O, Isaeva E, Levchenko V, Khedr S, Blass G, Ilatovskaya DV, Cowley AW Jr, Staruschenko A


Allen W. Cowley Jr PhD Professor in the Physiology department at Medical College of Wisconsin
Olena Isaeva PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Biological Transport, Active
Diabetes Mellitus, Type 1
Diabetic Nephropathies
Epithelial Sodium Channels
Gene Knockout Techniques
NADPH Oxidase 4
Rats, Inbred Dahl