キシ　セイジ   Seiji Kishi   岸　誠司    所属   川崎医科大学  医学部 臨床医学　腎臓・高血圧内科学    職種   特任准教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Insights into the Regulation of GFR by the Keap1-Nrf2 Pathway.
掲載誌名	正式名：Kidney360 略　 称：Kidney360 ISSNコード：26417650/26417650
掲載区分	国外
巻・号・頁	4(10),pp.1454-1466
著者・共著者	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
発行年月	2023/10
概要	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