Bhussry Seminar Series – “The Force Awakens: Mechanoregulated Ion Transport in the Distal Nephron”

Presentation: “The Force Awakens: Mechanoregulated Ion Transport in the Distal Nephron”

Speaker: Lisa M. Satlin, MD
Professor and System Chair of Pediatrics, Icahn School of Medicine at Mount Sinai (ISMMS)
Pediatrician-in-Chief, Mount Sinai Kravis Children’s Hospital (KCH) in NYC

Sponsored by the Department of Biochemistry and Molecular & Cellular Biology

Abstract:

An increase in tubular fluid flow rate (TFFR) within the aldosterone sensitive distal nephron (ASDN) of the mammalian kidney, as occurs in response to volume expansion or administration of diuretics, subjects cells therein to hydrodynamic forces, including fluid shear stress, circumferential stretch and drag/torque on cilia and microvilli/microplicae. An increase in TFFR leads to a biphasic increase in cell Ca2+ concentration ([Ca2+]i) in ASDN cells, due to release of IP3-sensitive internal Ca2+ stores coupled to extracellular Ca2+ entry at the basolateral membrane, and luminal Ca2+ entry. The flow-induced increase in [Ca2+]i activates BK channel-mediated flow-induced K+ secretion (FIKS) in the ASDN. Recent studies in mice with targeted disruption of the pore-forming BKα subunit solely in ASDN intercalated cells (IC-BKα-KO) confirm a critical role of this specific cell in FIKS. Additional evidence now suggests that Piezo1, a mechanosensitive, Ca2+ permeable channel expressed along the basolateral membranes of cells in the mouse ASDN, mediate TFFR-induced basolateral Ca2+ entry into intercalated cells, a key trigger for activation of BK channels and FIKS.