Tamaki Sasaki
   Department   Kawasaki Medical School  Kawasaki Medical School, Department of General Medicine,
   Position   Professor with Special Assignment
Article types 原著
Language English
Peer review Peer reviewed
Title Insights into the Regulation of GFR by the Keap1-Nrf2 Pathway.
Journal Formal name：Kidney360
Abbreviation：Kidney360
ISSN code：26417650/26417650
Domestic / ForeginForegin
Volume, Issue, Page 4(10),pp.1454-1466
Author and coauthor Kengo Kidokoro, Hiroyuki Kadoya, David Z I Cherney, Megumi Kondo, Yoshihisa Wada, Reina Umeno, Seiji Kishi, Hajime Nagasu, Kojiro Nagai, Takafumi Suzuki, Tamaki Sasaki, Masayuki Yamamoto, Yashpal S Kanwar, Naoki Kashihara
Publication date 2023/10
Summary KEY POINTS:Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1-NF (erythroid-derived 2)–like 2 pathway increases GFR without an appreciable increase in intraglomerular pressure. Kelch-like ECH-associated protein 1-NF (erythroid-derived 2)–like 2 pathway regulates GFR through changes in filtration area by modulating calcium dynamics and contractility in glomerular cells.BACKGROUND:Literature data suggest that the activation of the Kelch-like ECH-associated protein 1 (Keap1)-NF (erythroid-derived 2)–like 2 (Nrf2) pathway increases GFR in patients with type 2 diabetes and CKD. However, the mechanisms whereby the Keap1-Nrf2 pathway regulates GFR are unknown.METHODS:Various renal physiological parameters were assessed in C57BL/6 mice (wild-type), Nrf2-deficient mice, and Nrf2-activated Keap1-knockdown mice. In addition, these parameters were assessed after the administration of receptor targeting agent (RTA) dh404 (CDDO‐dhTFEA), an Nrf2 activator.RESULTS:Pharmacologic and genetic Keap1-Nrf2 activation increased renal blood flow (P < 0.05), glomerular volume (P < 0.05), and GFR (P < 0.05) but did not alter the afferent-to-efferent arteriolar diameter ratio or glomerular permeability. Calcium influx into the podocytes through transient receptor potential canonical (TRPC) channels in response to H2O2 was suppressed by Keap1-Nrf2 activation and TRPCs inhibition. Treatment with a TRPC6 and TRPC5 inhibitors increased single-nephron GFR in wild-type mice.CONCLUSIONS:In conclusion, the Keap1-Nrf2 pathway regulates GFR through changes in ultrafiltration by modulating redox-sensitive intracellular calcium signaling and cellular contractility, mediated through TRPC activity, in glomerular cells, particularly the podocytes.
DOI 10.34067/KID.0000000000000171
PMID 37265366