TY - JOUR
T1 - NOX4-dependent regulation of ENaC in hypertension and diabetic kidney disease
AU - Pavlov, Tengis S.
AU - Palygin, Oleg
AU - Isaeva, Elena
AU - Levchenko, Vladislav
AU - Khedr, Sherif
AU - Blass, Gregory
AU - Ilatovskaya, Daria V.
AU - Cowley, Allen W.
AU - Staruschenko, Alexander
N1 - Funding Information:
This research was supported by the National Heart, Lung, and Blood Institute grants: R35 HL135749, P01 HL116264 (AWC and AS), R01 HL122662 (AWC and AS), R00 HL116603 (TSP), R00 DK105160 (DVI), American Heart Association grants: 16EIA26720006 (AS), and 17SDG33660149 (O. P.), American Society of Nephrology Carl W. Gottschalk Grant (TSP), Dialysis Clinic Inc Reserve Fund C‐4153 (DVI), and Department of Veteran Affairs grant I01 BX004024 (to AS).
Funding Information:
This research was supported by the National Heart, Lung, and Blood Institute grants: R35 HL135749, P01 HL116264 (AWC and AS), R01 HL122662 (AWC and AS), R00 HL116603 (TSP), R00 DK105160 (DVI), American Heart Association grants: 16EIA26720006 (AS), and 17SDG33660149 (O. P.), American Society of Nephrology Carl W. Gottschalk Grant (TSP), Dialysis Clinic Inc Reserve Fund C-4153 (DVI), and Department of Veteran Affairs grant I01 BX004024 (to AS).
Publisher Copyright:
© 2020 Federation of American Societies for Experimental Biology
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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.
AB - 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.
KW - ENaC
KW - HO
KW - NOX4
KW - chronic kidney disease
KW - diabetic nephropathy
KW - salt-sensitive hypertension
UR - http://www.scopus.com/inward/record.url?scp=85089380202&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85089380202&partnerID=8YFLogxK
U2 - 10.1096/fj.202000966RR
DO - 10.1096/fj.202000966RR
M3 - Article
C2 - 32799394
AN - SCOPUS:85089380202
SN - 0892-6638
VL - 34
SP - 13396
EP - 13408
JO - FASEB Journal
JF - FASEB Journal
IS - 10
ER -