Table 1. The expression and function of ion channels in various ARPKD and ADPKD models vs healthy renal epithelia.
| ADPKD or ARPKD | Model/species | Effector/force | Action/effect | Changes in expression level of mRNA/protein for the channel/transporter of interest | Reference |
|---|---|---|---|---|---|
| ENaC | |||||
| ADPKD | Pkd1-knockout mice/mouse | VX-809, a corrector of CFTR | VX-809 ↓cyst growth | ↓ αENaC protein reduced in Pkd1-null mice; VX-809 restored αENaC apical membrane localization | [39] |
| M1 renal monolayers/mouse | P2X7 (αβmeATP) | P2X7 stimulation ↓ ENaC activity | N/A | [122] | |
| ARPKD | Immortalized cells of ARPKD renal cysts/human | ↑ amiloride-sensitive Na+ absorption compared with control cells | ↑ αENaC both mRNA and protein vs control cells | [133] | |
| PCK rat kidney; primary cultured PCK CD cells/rat | Mislocalization of E3 ubiquitin-protein ligase Nedd 4-2 | ↑ Amiloride-sensitive Na+ reabsorption vs control rats | ↑ α, β, γ ENaC protein vs control rats | [133] | |
| Cilium-deficient orpk CCD principal cell monolayers/mouse | Tg737orpk mutation | ↑ Amiloride and benzamil-sensitive ENaC-mediated Na+ absorption vs control mouse | N/A | [134] | |
| CD principal cells from Bpk ARPKD mice/mouse | N/A | ↓ Amiloride-sensitive ENaC-mediated Na+ absorption vs normal mice | αENaC mRNA detected, changes vs normal mice not tested | [135] | |
| Primary monolayer cultures of cystic CD principal cells/mouse | Mislocalization of apical EGF receptors; EGF | ↓ Na+ transport | ↓ αENaC mRNA vs non-cystic cells | [136] | |
| PCK rats/rat | Salt-deficient diet (SD) | ↑ cyst growth, ↑ miR-9a-5p in SD diet-fed group vs normal and high salt-fed groups | ↑ α, β, γ ENaC mRNA, ↓ αENaC protein in SD diet fed group vs normal and high salt-fed groups | [130] | |
| ARPKD cysts from PCK rats/rat | Benzamil | ↓ ENaC activity; ↑ cyst growth in 4- or 12-week benzamil-treated PCK rats | ↓ β-ENaC protein | [129] | |
| PCK rats/rat | P2x7 receptor knockout | ↓ ENaC activity; P2rx7 knockout ↑ENaC activity, ↓cyst growth vs littermate PCK rats | N/A | [123] | |
| Pannexin-1 | |||||
| ADPKD | Pkd1 knockout mice (iKsp-Pkd1−/−)/mouse | Fluid shear stress (FSS) | ↑FSS-sensitive ATP release | ↑mRNA expression | [124] |
| Pkd1−/− distal convoluted tubule 15 (mDCT15) cells/mouse | FSS; Pannexin-1 inhibition by BB-FCF or knockout | ↑FSS-sensitive ATP release; Pannexin-1 inhibition (by BB-FCF) or knockout ↓FSS sensitive ATP release | ↑mRNA expression | [124] | |
| zebrafish pkd2 morphants (pkd2-MO) | BB-FCF (Pannexin-1 inhibitor) | Pannexin-1 inhibition attenuated cyst growth | N/A | [124] | |
| Pkd1RC/RC mouse kidneys/mouse; M1 renal monolayers/mouse | 50 μM probenecid (PANX1 blocker) | ↑ cyst growth; probenecid treatment of M-1 cells ↓shear-stress-stimulated ATP release | ↑protein | [122] | |
| CFTR | |||||
| ADPKD | ADPKD kidneys and primary cultured ADPKD cells/human | N/A | N/A | mRNA; protein, apical localization detected in cystic cells | [38] |
| CD-derived mCCD-N21 cells/mouse | Forskolin, CPT-cAMP, a membrane-permeable cAMP analog (cAMP-elevating agents); NPPB, 50–100 μM or CFTRinh172, 10–20 μM (CFTR Inhibitors) | ↑tubule enlargement and cyst formation; NPPB ↓ tubule enlargement and cyst formation, in part inhibited aldosterone- and/or vasopressin-induced Isc | mRNA detected | [51] | |
| Primary cultures of ADPKD cells/human | Forskolin; CPT-cAMP, a membrane-permeable cAMP analog; glibenclamide, 200 μM; DPC, 500 μM (CFTR channel inhibitors) | ↑ activity of CFTR channel; glibenclamide, DPC inhibit Cl− currents | protein, apical membrane localization detected | [35] | |
| MDCK cell model/dog embryonic kidney cyst model (Pkd1 knockout)/mouse | Thiazolidinone tetrazolo-CFTRinh172, glycine hydrazide Ph-GlyH-101 (CFTR inhibitors), IC50 > 3 μM | ↓ 8-Br-cAMP-induced cyst number and growth | N/A | [44] | |
| Embryonic kidney organ culture model of PKD/mouse | Pyrimido-pyrrolo-quinoxalinedione PPQ-102, IC50 ∼ 90 nM | ↓ 8-Br-cAMP-induced cyst number and growth | N/A | [43] | |
| PKD1−/− metanephric kidneys; embryonic kidneys with 8-Br-cAMP-induced cysts/mouse | Thiazolidinone CFTRinh172, 100 μM | ↓ cyst formation, Cftr−/− genotype completely blocked cyst formation in Pkd−/− kidneys | N/A | [52] | |
| PKD1-knockout mice/mouse | VX-809, a corrector of CFTR | VX-809 increases CFTR at the apical membrane, but most strongly at the basolateral membrane | Protein, apical membrane localization detected | [39] | |
| Principal-like (pl)MDCK cyst model/canine | Pkd1-knockout cells; CFTRinh172, 10 μM (CFTR inhibitor) | ↑Cl− secretion, cyst size; ↓ cyst growth in the presence of forskolin by inhibition of CFTR | ↑Protein | [40] | |
| MDCK cyst model/canine | Knockdown of CFTR, CFTRinh172, 10 μM | ↓ cyst growth | N/A | [50] | |
| ARPKD | BPK ARPKD mice/mouse | CFTR knockout | The loss of CFTR does not alter the course of ARPKD cystic disease | N/A | [44] |
| Pkhd1del4/del4 cholangiocytes/mouse | VX-809 (CFTR corrector), heat shock proteins: ↑ HSP27 or ↓HSP70 or HSP90 | ↑ forskolin-induced cyst growth, altered colocalization of CFTR with both apical and basolateral membranes; VX-809 and HSPs ↓cyst growth and restored CFTR localization toward normal values | ↓ protein | [43] | |
| TMEM16A (anoctamin 1) | |||||
| ADPKD | Principal-like MDCK cyst model/dog; ADPKD tissue/human; Metanephric kidney cyst model/mouse | Forskolin (adenylyl cyclase agonist), UTP, ATP; tannic acid AO1 (selective inhibitor of anoctamin 1) Knockdown of anoctamin 1 | UTP ↑ Cl− secretion; AO1 or knockdown of anoctamin 1 ↓ Ca2+-dependent Cl− secretion; in metanephric kidney: knockdown and inhibitors ↓ forkolin-induced cyst growth | Forskolin ↑protein in the apical membrane, mRNA detected | [47] |
| Renal CD principle cells from dog (MDCK)/canine and M1/mouse | Knockdown of Pkd1 or Pkd2 ATP, UTP | ↑ intracellular Ca2+ ([Ca2+]i) signals, purinergic Ca2+ release from ER, Cl− secretion and cyst cell proliferation | ↑mRNA, ↑protein | [47] | |
| Principal-like MDCK cyst model/dog | Pkd1-knockout cells; niclosamide (TMEM16A inhibitor) | ↑Cl− secretion, [Ca2+]i and cyst cell proliferation; ↓ cyst growth in the presence of niclosamide | ↑protein | [40] | |
| Pkd1 knockout mice/mouse | Niclosamide benzbromarone Ani9 (TMEM16A specific inhibitor) | ↓ cyst growth and cyst cell proliferation | ↑protein | [40] | |
| Pkd1/Tmem16a double knockout mice/mouse | Pkd1/Tmem16a double knockout | ↓ cyst growth and cyst cell proliferation | ↓protein | [40] | |
| Tissue samples from patients with ADPKD/human, embryonic PKD1−/− kidney cultures/mouse, MDCK cyst model/dog | ROS, peroxidation of plasma membrane phospholipids (e.g. tert-butyl hydroperoxide (tBHP)), ATP, UTP; scavengers of ROS glutathione, coenzyme Q10; ferrostatin-1; idebenone, AO1; knockdown of T16A | ↑activity of TMEM16A, cyst growth, Ca2+ signaling, Ca2+-sensitive adenylate cyclase ADCY1; scavengers of ROS delay cyst enlargement, ↓activation of TMEM16A | ↑protein | [50] | |
| Primary renal epithelial cells isolated from Pkd1 knockout mice/mouse | Gender | Basal [Ca2+]i higher in males compared with females, ↑basal and ATP-stimulated Cl− currents, ↑ cell proliferation and cyst development in male kidneys | Protein level not different between male and female | [126] | |
| NKCC1 | |||||
| ADPKD | ADPKD kidneys and primary cultured ADPKD cells/human | N/A | N/A | mRNA detected; protein-basolateral localization (in same cells where CFTR is also expressed) | [38] |
| CD-derived mCCD-N21 cells/mouse | Bumetanide or ethacrynic acid (NKCC1 inhibitors) | ↓ AVP- and aldosterone-stimulated short-circuit current, tubular enlargement and cyst formation | Aldosterone ↑ mRNA expression, forskolin didn't change mRNA level | [51] | |
| PKD1−/− metanephric kidneys, Embryonic kidneys with cAMP-induced cysts/mouse | Bumetanide | ↓ Cyst formation | Protein detected | [52] | |
| Kir 6.2 (KCNJ11) | |||||
| ADPKD | Cells derived from the cysts of patients with ADPKD/human | Glibenclamide, 25–100 μM (inhibitor of ATP-sensitive K+ channels and CFTR) | Glibenclamide modestly decreased forskolin-stimulated current at the apical membrane. Its basolateral application ↓Isc to a greater extent. ↓ cyst growth and proliferation | mRNA detected | [138] |
| Ca2+-dependent KCa3.1 (SK4, KCNN4) | |||||
| ADPKD | MDCK/dog; kidney cells derived from patients with ADPKD/human | Forskolin, DCEBIO (KCa3.1 activator); TRAM-34, overexpression of myotubularin-related protein-6 (specific KCa3.1 blockers) | ↑anion secretion, KCa3.1 channel activity, in vitro cyst growth; ↓anion secretion, in vitro cyst formation and enlargement | mRNA detected | [139] |
| Principal-like MDCK cyst model/canine | Clotrimazole (SK4 inhibitor) | ↓ ATP, UTP-induced Cl− secretion | N/A | [47] | |
| TRPV4 | |||||
| ADPKD | Primary ADPKD cells/human | Flow | ↓TRPV4 activity, basal [Ca2+]i, loss of flow-induced [Ca2+]i signaling compared with normal kidney (NK) cells | Protein expression did not change vs NK cells; TRPV4 glycosylation was reduced in ADPKD cells | [62] |
| ARPKD | CD cysts derived from PCK rats/rat | Flow; GSK1016790A (selective TRPV4 activator) | ↓TRPV4 activity, basal [Ca2+]i, loss of flow-induced [Ca2+]i signaling compared with normal kidney cells; GSK1016790A restored mechanosensitive Ca2+ signaling and TRPV4 function | ↓Protein, TRPV4 glycosylation, subcellular TRPV4 localization is shifted toward the apical membrane; GSK1016790A restored subcellular TRPV4 distribution | [64] |
Abbreviations: ENaC, epithelial Na+ channel; FSS, fluid shear stress; HSP, heat shock protein; KCNJ11, ATP-sensitive K+ channel, Kir 6.2; NKCC1, Na+-K+-2Cl− cotransporter; PANX1, Pannexin-1; TMEM16A, transmembrane member 16A; TRPV4, transient receptor potential vanilloid type 4.