Regulation of cation transport in the distal nephron by mechanical forces

Abstract

Thiazide and loop diuretics induce renal K(+) secretion, often leading to renal K(+) wasting and hypokalemia. This phenomenon has been proposed to reflect an increase in delivery to and reabsorption of Na(+) by the distal nephron, with a resultant increase in the driving force for passive K(+) efflux across the apical membrane. Recent studies suggest that cellular mechanisms that lead to enhanced rates of Na(+) reabsorption as well as K(+) secretion in response to increases tubular flow rates are more complex. Increases in tubular flow rates directly enhance the activity of apical membrane Na(+) channels and indirectly activate a class of K(+) channels, referred to as maxi-K, that are functionally inactive under low flow states. This review addresses the role of biomechanical forces, generated by variations in urinary flow rate and tubular fluid volume, in the regulation of transepithelial Na(+) and K(+) transport in the distal nephron. The question of why the distal nephron has evolved to include a component of flow-dependent K(+) secretion is also addressed.

Protein Kinase G Inhibits Flow-Induced Ca2+ Entry into Collecting Duct Cells

“…However, we could not completely rule out the involvement of protein kinase C (K i =4 mM). 15 2,6 In the present study, we found that atrial natriuretic peptide and nitric oxide, through their action on PKG, inhibited the flow-induced [Ca 2+ ] i entry in M1-CCD cells. Previously, atrial natriuretic peptide and nitric oxide were known to inhibit Na + reabsorption in CCD.…”

“…4,5 However, high tubular flow stimulates K + secretion in the CCD. 2,6 An important early signal for flow response is the rise of cytosolic Ca 2+ ([Ca 2+ ] i ) in CCD epithelial cells. Evidence suggests that these [Ca 2+ ] i rises are requisite for flow-induced K + secretion in these cells.…”

“…Evidence suggests that these [Ca 2+ ] i rises are requisite for flow-induced K + secretion in these cells. 2,6 There is intense interest in searching for the plasma membrane channels that mediate flow-induced Ca 2+ entry in renal epithelial cells. Several candidate channels have been proposed, including transient receptor potential vanilloid 4 (TRPV4), 7,8 transient receptor potential polycystin 1 (TRPP1)-TRPP2 complex, 9 and heteromeric TRPV4-P2 channels.…”

Opening lines of communication in the distal nephron

“…In this context, K + secretion is mediated by the luminal large-conductance Ca 2+ -activated K + channel (referred to as the BK channel) and the basolateral Na + /K + /2Cl -cotransporter (7,8). The findings that both individuals with Bartter syndrome as a result of ROMK loss-of-function mutations and mice lacking ROMK expression have robust renal K + secretion highlight the importance of this BK channel-mediated K + secretory pathway (9).…”

TRPV4 Dysfunction Promotes Renal Cystogenesis in Autosomal Recessive Polycystic Kidney Disease

“…[10][11][12] It is accepted that the CD cells elevate [Ca 2+ ] i in response to mechanical stress arising from variations in tubular flow or tubular composition. [13][14][15][16][17][18][19][20][21][22][23] Impaired mechanosensitive [Ca 2+ ] i responses, reported for both cultured ADPKD 24 and ARPKD 25,26 cells, point to a possible fundamental role of disrupted [Ca 2+ ] i signaling in cystogenesis. The central cilia and cilia-associated PC1 and PC2 were proposed to mediate flow-induced cellular responses.…”