PS-BPB08-6: REGULATORY MECHANISM OF GLOMERULAR FILTRATION RATE BY THE KEAP1/NRF2 PATHWAY

Abstract

The activation of the Kelch like ECH associated protein 1 (Keap1)/nuclear factor (erythroid derived 2) like 2 (Nrf2) pathway increases glomerular filtration rate (GFR) in patients with type 2 diabetes and chronic kidney disease. However, the mechanisms whereby the Keap1/Nrf2 pathway regulates GFR are unknown. C57BL/6 mice (WT), Nrf2 deficient mice, and Nrf2 activated Keap1 knockdown mice were compared, and RTA dh404 (CDDO dhTFEA) was used as a Nrf2 activator. Glomerular hemodynamics and the permeability of glomeruli to macromolecules were evaluated using laser Doppler techniques and in vivo imaging. Calcium influx and the rearrangement of the actin cytoskeleton in response to angiotensin II, H2O2, the Nrf2 activator dh404, and transient receptor potential cation channel, subfamily C (TRPC) channel inhibitors were evaluated in podocytes. Finally, the effects of a TRPC6 inhibitor on GFR were investigated in vivo. Pharmacological 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 afferent or efferent arteriolar diameter or glomerular permeability. Calcium influx into podocytes through TRPC channels in response to angiotensin II or H2O2 was suppressed by Keap1/Nrf2 activation. TRPC inhibitors and dh404 reduced the activation of the small GTPase(RhoA)/Rho associated kinase 1/LIM domain kinase 1/cofilin pathway and the subsequent actin rearrangement induced by angiotensin II or H2O2. Treatment with a TRPC6 inhibitor increased single nephron GFR in WT mice. In conclusion, the Keap1/Nrf2 pathway regulates GFR through changes in ultrafiltration via intracellular calcium signaling and cellular contractility, mediated through TRPC activity, in glomerular cells.