NOX4-dependent regulation of ENaC in hypertension and diabetic kidney disease

Tengis S. Pavlov, Oleg Palygin, Elena Isaeva, Vladislav Levchenko, Sherif Khedr, Gregory Blass, Daria V. Ilatovskaya, Allen W. Cowley, Alexander Staruschenko

Research output: Contribution to journalArticlepeer-review

11 Scopus 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 H2O2 upregulated ENaC activity, and H2O2 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.

Original languageEnglish (US)
Pages (from-to)13396-13408
Number of pages13
JournalFASEB Journal
Issue number10
StatePublished - Oct 1 2020


  • ENaC
  • HO
  • NOX4
  • chronic kidney disease
  • diabetic nephropathy
  • salt-sensitive hypertension

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics


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