Insulin Inhibits Nrf2 Gene Expression via Heterogeneous Nuclear Ribonucleoprotein F/K in Diabetic Mice.
Oxidative stress induces endogenous antioxidants via nuclear factor erythroid 2-related factor 2 (Nrf2), potentially preventing tissue injury. We investigated whether insulin affects renal Nrf2 expression in type 1 diabetes (T1D) and studied its underlying mechanism. Insulin normalized hyperglycemia, hypertension, oxidative stress, and renal injury; inhibited renal Nrf2 and angiotensinogen (Agt) gene expression; and upregulated heterogeneous nuclear ribonucleoprotein F and K (hnRNP F and hnRNP K) expression in Akita mice with T1D. In immortalized rat renal proximal tubular cells, insulin suppressed Nrf2 and Agt but stimulated hnRNP F and hnRNP K gene transcription in high glucose via p44/42 mitogen-activated protein kinase signaling. Transfection with small interfering RNAs of p44/42 MAPK, hnRNP F, or hnRNP K blocked insulin inhibition of Nrf2 gene transcription. Insulin curbed Nrf2 promoter activity via a specific DNA-responsive element that binds hnRNP F/K, and hnRNP F/K overexpression curtailed Nrf2 promoter activity. In hyperinsulinemic-euglycemic mice, renal Nrf2 and Agt expression was downregulated, whereas hnRNP F/K expression was upregulated. Thus, the beneficial actions of insulin in diabetic nephropathy appear to be mediated, in part, by suppressing renal Nrf2 and Agt gene transcription and preventing Nrf2 stimulation of Agt expression via hnRNP F/K. These findings identify hnRNP F/K and Nrf2 as potential therapeutic targets in diabetes.
Department of Medicine, Université de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.
Anindya
A
Ghosh
Department of Medicine, Université de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.
Shaaban
S
Abdo
Department of Medicine, Université de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.
Shuiling
S
Zhao
Department of Medicine, Université de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.
Chin-Han
CH
Wu
Department of Medicine, Université de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.
Yixuan
Y
Shi
Department of Medicine, Université de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.
Chao-Sheng
CS
Lo
Department of Medicine, Université de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.
Isabelle
I
Chenier
Department of Medicine, Université de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.
Thierry
T
Alquier
Department of Pathology and Cell Biology, Université de Montréal and Centre de recherche, Hôpital Maisonneuve-Rosemont, Montreal, Quebec, Canada.
Janos G
JG
Filep
Pediatric Nephrology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Julie R
JR
Ingelfinger
Department of Medicine, Université de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.
Shao-Ling
SL
Zhang
Department of Medicine, Université de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.
John S D
JSD
Chan
D000808:Angiotensinogen / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H / Q000235:genetics* / Q000378:metabolism; D034641:Heterogeneous-Nuclear Ribonucleoprotein K / Q000235:genetics* / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology* / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects*
D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D007328:Insulin; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000808:Angiotensinogen; D020928:Mitogen-Activated Protein Kinases