Insights into the Regulation of GFR by the Keap1-Nrf2 Pathway

Abstract

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.