The renal TRPV4 channel is essential for adaptation to increased dietary potassium

Abstract

To maintain potassium homeostasis, kidneys exert flow-dependent potassium secretion to facilitate kaliuresis in response to elevated dietary potassium intake. This process involves stimulation of calcium-activated large conductance maxi-K (BK) channels in the distal nephron, namely the connecting tubule and the collecting duct. Recent evidence suggests that the TRPV4 channel is a critical determinant of flow-dependent intracellular calcium elevations in these segments of the renal tubule. Here, we demonstrate that elevated dietary potassium intake (five percent potassium) increases renal TRPV4 mRNA and protein levels in an aldosterone-dependent manner and causes redistribution of the channel to the apical plasma membrane in native collecting duct cells. This, in turn, leads to augmented TRPV4-mediated flow-dependent calcium ion responses in freshly isolated split-opened collecting ducts from mice fed the high potassium diet. Genetic TRPV4 ablation greatly diminished BK channel activity in collecting duct cells pointing to a reduced capacity to excrete potassium. Consistently, elevated potassium intake induced hyperkalemia in TRPV4 knockout mice due to deficient renal potassium excretion. Thus, regulation of TRPV4 activity in the distal nephron by dietary potassium is an indispensable component of whole body potassium balance.

Deficient transient receptor potential vanilloid type 4 function contributes to compromised [Ca2+] homeostasis in human autosomal‐dominant polycystic kidney disease cells

“…1 and 3) in primary cultured human kidney cells that are of predominantly distal tubule origin (35). We found that TRPV4 function was identical to that reported in freshly isolated distal tubules of mice and rats (10,28,29), which points to a high level of conservation of molecular determinants conferring mechanosensitivity to renal tubule cells between rodents and humans. Considering that the kidney exhibits the highest level of TRPV4 expression compared with other tissues and organs (26), targeting channel activity could be a relatively specific strategy by which to regulate [Ca 2+ ] i signaling in renal epithelial cells.…”

“…Whereas TRPV4 can be detected in many epithelial tissues, including lung, spleen, skin, sweat glands, as well as in other organs (23)(24)(25)(26)(27), expression of the channel is much higher in the kidney (26). We have previously demonstrated that TRPV4 is essential for mediating flowdependent [Ca 2+ ] i elevations in the connecting tubule and CD (28)(29)(30). Furthermore, it was reported that TRPV4 predominantly exists as a heterotetramer with PC2 in a 2:2 presumable stoichiometry (31) that forms a 23-pS Ca 2+ -permeable channel at the apical membrane of CD cells (32,33).…”

Aldosterone, SGK1, and ion channels in the kidney

“…Recently, it has been demonstrated that both aldosterone and high K + diets increase the total expression of TRPV4 in primary and immortalized mouse CCD cells [ 84 ]. It was notable that TRPV4 expression in mice treated with MR antagonists was below control, implying that aldosterone constitutively regulates TRPV4 [ 84 ].…”

“…Recently, it has been demonstrated that both aldosterone and high K + diets increase the total expression of TRPV4 in primary and immortalized mouse CCD cells [ 84 ]. It was notable that TRPV4 expression in mice treated with MR antagonists was below control, implying that aldosterone constitutively regulates TRPV4 [ 84 ]. This study further demonstrated that high K + diets, which should induce aldosterone release [ 85 ], increased TRPV4 apical membrane expression and increased flow-mediated [Ca 2+ ] i [ 84 ].…”

“…It was notable that TRPV4 expression in mice treated with MR antagonists was below control, implying that aldosterone constitutively regulates TRPV4 [ 84 ]. This study further demonstrated that high K + diets, which should induce aldosterone release [ 85 ], increased TRPV4 apical membrane expression and increased flow-mediated [Ca 2+ ] i [ 84 ]. While SGK1-mediated effects were not explored, the authors noted that prior findings of TRPV4 phosphorylation (at Ser 824 ) by SGK1, which increased channel activity, Ca 2+ influx, and protein stability [ 86 ], would explain their aldosterone-mediated effects 84].…”