Connexin 43: A Target for the Treatment of Inflammation in Secondary Complications of the Kidney and Eye in Diabetes
Abstract
:1. Introduction
2. Targeting Inflammation in Microvascular Complications of Diabetes
3. Cx43 Hemichannel Blockers and Treatment of Inflammation in Diabetes and Its Secondary Complications
4. Cx43 Hemichannels and Treatment of Inflammation in Diabetic Kidney Disease
5. The Therapeutic Potential of Blocking Cx43 in Diabetic Retinopathy
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Hemichannel Blocker/ Therapeutic Agent | Sequence/ Formula | Mechanism of Action | Examples of Models Trialled in | Clinical Trials? |
---|---|---|---|---|
Gap19 | KQIEIKKFK Also: Transactivator of transcription (TAT)-Gap19 -YGRKKRRQRRR-KQIEIKKFK Xentry (XG19) -lclrpvGG-KQIEIKKFK | Binds to the intracellular loop of Cx43, whilst not affecting gap junction communication [115]. Exhibits low cell permeability, so is often coupled with TAT which aids transcription or Xentry which is a cell penetrating peptide [116]. | Primary mouse cardiomyocytes [117]; Cerebral ischaemia/injury in mice [118]; Primary mouse astrocytes/hippocampal slices (TAT-Gap19) [115]; Immortalised human retinal pigment epithelium cells (ARPE-19)/primary human retinal microvascular endothelial cells (hREMC) (XG19) [116]; Isolated rat hepatocytes [119]; Human gingival fibroblasts [120]. | None found. |
Gap26 | VCYDKSFPISHVR | Originally developed to block gap junction communication [121]. Now shown to also block hemichannels, Gap26 binds to the first extracellular loop of Cx43 [112]. | Isolated pig ventricular cardiomyocytes [117]; Cultured microglia, astrocytes and neurons [122]. | None found. |
Gap27 | SRPTEKTIFII | Originally designed for gap junction blockade [121], Gap27 can also block hemichannels by binding to the second extracellular loop of Cx43 [112]. | Isolated pig ventricular cardiomyocytes [117]; Primary human corneal epithelial cells in vitro, human corneas ex vivo rat wound healing model in vivo [123]; Adult keratinocytes, juvenile foreskin, human neonatal fibroblasts and adult dermal tissue as models of wound healing [124]. | None found. |
Peptide 5 | VDCFLSRPTEKT | Binds to the second extracellular loop of Cx43, preventing hemichannel opening [111]. | Human primary proximal tubule epithelial cells and clonal tubular kidney epithelial cells [108]; Retinal pigment epithelial cells [105,125]; Patch-clamp inflammatory model in mice [102]; Light-damaged albino rat model [126]. | None found |
Tonabersat (Xiflam) | C₂₀H₁₉ClFNO₄ | Able to block gap junctions (at high concentration), this small molecule, a benzopyran derivative can block Cx43 hemichannels at lower doses [50]. | Human retinal pigment epithelial cells (ARPE-19) [50]; Rat model of diabetic retinopathy [127]. | Phase II clinical trials in migraines-NCT00311662 NCT00534560 NCT00332007 |
alpha connexin carboxyl terminus 1 (αCT1) | Ant-RPRPDDLEI | Binds to the COOH tail (cytoplasmic terminus) of Cx43 [113], mediating phosphorylation of Cx43 at serine 368 [128]. Has also been shown to affect gap junction remodelling [129]. | Rat model corneal wound [130]; Beneficial in a randomised control trial assessing cutaneous scarring [131]; Human biopsy tissue/rat and guinea pig scars [132]. | Clinical trials for diabetic foot ulcers as ‘Grannexin gel’ Phase I-NCT02652754 Phase II-NCT02652572 Terminated at phase III May 2020 (NCT02667327)–no safety concerns |
Danegaptide (GAP-134) | C14H17N3O4 | Not fully elucidated. As a gap-junction modifier, it maintains gap junction coupling during cellular stress [133,134], and has been shown to block Cx43 hemichannels in human proximal tubule epithelial cells [135]. | Primary human proximal tubule epithelial cells [135]; Rat Retinal Endothelial cells during high glucose stress [134]; Myocardial infarct in pigs [136] and dogs [137]; Atrial fibrillation models in dogs [138,139]. | Phase II for myocardial infarction-NCT01977755 |
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Cliff, C.L.; Williams, B.M.; Chadjichristos, C.E.; Mouritzen, U.; Squires, P.E.; Hills, C.E. Connexin 43: A Target for the Treatment of Inflammation in Secondary Complications of the Kidney and Eye in Diabetes. Int. J. Mol. Sci. 2022, 23, 600. https://doi.org/10.3390/ijms23020600
Cliff CL, Williams BM, Chadjichristos CE, Mouritzen U, Squires PE, Hills CE. Connexin 43: A Target for the Treatment of Inflammation in Secondary Complications of the Kidney and Eye in Diabetes. International Journal of Molecular Sciences. 2022; 23(2):600. https://doi.org/10.3390/ijms23020600
Chicago/Turabian StyleCliff, Chelsy L., Bethany M. Williams, Christos E. Chadjichristos, Ulrik Mouritzen, Paul E. Squires, and Claire E. Hills. 2022. "Connexin 43: A Target for the Treatment of Inflammation in Secondary Complications of the Kidney and Eye in Diabetes" International Journal of Molecular Sciences 23, no. 2: 600. https://doi.org/10.3390/ijms23020600