Table 1.
Actions of Klotho on various cells, pathways, and proteins that are involved in inflammatory and fibrotic processes in diabetes and diabetic nephropathy, with their reciprocal actions on the Klotho protein.
| Cell/Pathway/Protein | Action of Klotho on the Cell/Pathway/Protein | Action of the Cell/Pathway/Protein on Klotho | Connections with Other Cells/Pathways/Proteins | Reference |
|---|---|---|---|---|
| T cells | Klotho downregulation causes T-cell infiltration of kidneys | [37] | ||
| T-helper cells (CD4+ lymphocytes, CD28 molecule) |
Klotho downregulation in CD4+ lymphocytes is associated with lower levels of CD28 molecule through an increase in TNF-α | TNF-α | [38] | |
| Macrophages | Klotho downregulation causes macrophage infiltration of kidneys | [37] | ||
| MCP-1 (CCL2)/CCR2, ICAM-1 | Klotho downregulation increases the expression of MCP-1 and ICAM-1 in the kidneys Klotho inhibits TXNIP-mediated expression of ICAM-1 |
PKC, TXNIP, IL-1β, TNF-α, RIG-I | [8,37,49,50] | |
| Complement system | Proteins of the complement system (C1, C5a), released during inflammation, inhibit Klotho expression | [53] | ||
| PI3K/Akt | Klotho blocks TNF-α-induced PI3K/Akt pathway to restrain NF-κB activation | TNF-α, NF-κB | [13] | |
| TNF-α, TWEAK | Klotho inhibits TNF- α actions on the intensification of inflammatory processes | TNF-α and TWEAK inhibit Klotho through NF-κB activation | PGC-1α, NF-κB | [39,42] |
| NF-κB and its p65 subunit (RelA) | Klotho inhibits NF-κB activity | NF-κB inhibits Klotho expression | p38 MAPK, JNK, PKC, TNF-α, IL-6, IL-8, IL-10, MCP-1, RANTES (CCL5) | [8,32,39,42,54] |
| IκBα | Klotho modulates IκBα function to inhibit RelA activation | NF-κB, RelA | [43] | |
| HSP70 | Klotho increases HSP70 levels, which inhibit NF-κB activation | NF-κB | [39] | |
| TLR4 | Klotho induces proteolytic degradation of TLR4 | TLR4 induces downregulation of Klotho expression | RIG-I, IL-1 β, MyD88, NF-κB, JNK, IKK, p38 MAPK, IRS | [8,45] |
| RIG-I | Klotho inhibits RIG-I | NF-κB, IL-6, IL-8, TLR4 | [50,51] | |
| IL-6, IL-8 | Klotho inhibits IL-6 and IL-8 through RIG-I and NF-κB suppression | RIG-I, NF-κB | [50,51] | |
| IL-1β, NLRP3 | Klotho inhibits vitamin D3 and TXNIP effect on IL-1β production and NLRP3-inflammasome activation | calcitriol, TXNIP | [49] | |
| IL-10 | Klotho increases IL-10 secretion | JAK2/STAT3, p38 MAPK, HuR, TNF-α, NF-κB | [40] | |
| Vitamin D3 in its bioactive form (calcitriol) | FGF23/Klotho pathway activation suppresses calcitriol production and promotes its degradation | Calcitriol stimulates expression of Klotho and FGF23 | FGF23 | [40,49,55] |
| TGF-β1 | Klotho binds to type II TGFβ receptors, thus inhibiting TGF-β1 signaling | Wnt, PGC-1α, MAPK, NF-κB, Smads | [54,56] | |
| Wnt/β-catenin | Klotho binds several Wnt protein family members, thus inhibiting canonical Wnt signaling | TGF-β1, PGE2 | [48] | |
| ROS | Klotho inhibits IGF-1 signaling cascade, thus causing the activation of FoxO transcription factors, induction of the expression of MnSOD, and removal of ROS Klotho suppresses TXNIP-dependent activation of the NLRP3 inflammasome in macrophages through the enhancement of FGF23 signaling |
TLR4, PGC-1α, IGF-1, FoxO, MnSOD, TXNIP, NLRP3, FGF23 | [48] | |
| NO | Klotho modulates NO metabolism and prevents its impairment | [48] |
CCR2, C-C chemokine receptor type 2; FGF23, fibroblast growth factor 23; FoxO, forkhead box transcription factors; HSP70, heat shock protein 70 kDa; HuR, Hu-antigen receptor; ICAM-1, intercellular adhesion molecule 1; IGF-1, insulin-like growth factor 1; IKK, IκB kinase; IL, interleukin; IRS, insulin receptor substrate; IκBα, nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor α; JAK2/STAT3, proteins of the Janus kinase-signal transducer and activator of transcription signaling pathway; JNK, c-Jun N-amino-terminal kinase; MBL, mannose binding lectin; MCP-1, monocyte chemoattractant protein 1, also referred to as chemokine (C-C motif) ligand 2 (CCL2); MnSOD, superoxide dismutase; MyD88, myeloid differentiation factor 88; NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells; NLRP3 inflammasome, a type of inflammasome that contains NACHT, LRR, and PYD domain-containing protein 3; NO, nitric oxide; p38 MAPK, p38 mitogen-activated protein kinase; PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1-α; PGE2, prostaglandin E2; PI3K/Akt, phosphatidylinositol 3-kinase/protein kinase B; PKC, protein kinase C; RANTES, regulated on activation, normal T cell expressed and secreted, also referred to as chemokine (C-C motif) ligand 5 (CCL5); RelA, nuclear factor NF-κB p65 subunit; RIG-I, retinoic acid-inducible gene I; ROS, reactive oxygen species; TGF-β1, transforming growth factor β1; TLR, Toll-like receptor; TNF-α, tumor necrosis factor α; TWEAK, tumor necrosis factor-like weak inducer of apoptosis; TXNIP, thioredoxin-interacting protein.