Title

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

Document Type

Article

Publication Date

8-16-2020

Publication Title

The FASEB journal

Abstract

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 H(2) O(2) upregulated ENaC activity, and H(2) O(2) production was reduced in both the renal cortex and medulla in SS(Nox4-/-) 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 SS(Nox4-/-) rats. NaCl cotransporter (NCC) expression was increased compared to healthy controls, while expression values between SS and SS(Nox4-/-) 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.

PubMed ID

32799394

ePublication

ePub ahead of print

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