Table 1 The summary of cellular crosstalk among glomerular endothelial cell, podocyte, and mesangial cells in DKD

GECs → MCs

Exosome containing TGF-β1 mRNA

TGF-β/Smads signaling pathways

Causing significant mesangial expansion, proliferation and ECM protein overproduction

[71, 72]

GECs → MCs

Exosomes enriched in circRNAs

PI3K/AKT signaling pathway, MAPK signaling pathway

Promoting α-SMA expression and inducing EMT in MCs

[72]

MCs → GECs

Integrin αvβ8 and its main ligand TGF-β

TGF-β/Smads signaling pathway (probably)

Reducing TGF-β binding; Causing bioactive TGF-β release, thus stimulating apoptosis of GECs

[73]

GECs → Podocytes

Exosome containing TGF-β1 mRNA

Wnt/β-catenin signaling pathway

Causing EMT and dysfunction of podocytes

[74]

GECs → Podocytes

Bone morphogenetic protein and activin membrane-bound inhibitor

TGF-β/ALK1-Smad1/5 signaling pathway

Worsening podocyte loss; Inducing proteinuria

[75]

MCs → Podocytes

Exosome containing TGF-β1 mRNA

TGF-β1/PI3K/AKT signaling pathway

Inducing podocytes’ apoptosis and inhibiting cell adhesion

[76]

Podocytes → GECs

Ang-1 expressed in podocytes; Tie-2 expressed in GECs

Ang-1/Tie-2 signaling pathway

Promoting the survival of GECs; Decreasing proteinuria; Preventing abnormal proliferation, angiogenesis, and migration of GECs

[77,78,79]

Podocytes → GECs

Ang-1 expression in podocytes; Tie-2 expressed in GECs

Ang-1/Tie-2 signaling pathway

Modulating podocyte injury responses and secretion of key angiogenic factors, thereby affecting GECs remodeling after injury

[79]

Podocytes → GECs

Ang-2 secreted by podocytes; Tie-2 expressed in GECs

Ang-2/Tie-2 signaling pathway

Leading to more proteinuria and apoptosis of GECs;

Inhibiting the maintenance of the integrity of GECs and filtration barrier function

[80]

ECs → MCs

Ang-2 increased and released from ECs under an HG condition;

Ang-2/Tie-2 signaling pathway; miR-33-5p-SOCS5 loop

Inducing MC apoptosis

[81]

Podocytes → GECs

VEGF-A produced by podocytes;

VEGF-A receptors on GECs named VEGFR-1 and VEGFR-2

VEGF signaling pathways

Maintaining endothelial fenestration, thereby preserving endothelial function

[82]

Podocytes → GECs

The HG condition up-regulated the production of VEGF-A in podocytes

VEGF signaling pathways

Leading to endothelial cell damage

[83]

GECs → Podocytes

GEC-derived excessive miR-200c; VEGF-A in podocytes

VEGF-A/VEGFR2 signaling pathways

Impairing glomerular homeostasis;

Leading to the damage of the glomerular;

Causing extensive foot process effacement and proteinuria

[84]

Podocytes → GECs

Beclin-1 in podocytes; VEGF-A secreted by podocytes

VEGF-A/VEGFR2 signaling pathways

Being indispensable for VEGF secretion;

Maintaining GFB function; Deleting Beclin-1 in podocytes led to early-onset glomerulosclerosis

[85]

Podocytes → GECs

Overexpressed Sema3A in mature podocytes

Sema3A/NRP1 signaling pathway; VEGF-A/NRP1 signaling pathways

Causing glomerular hypoplasia and apoptosis of GECs

[86]

Podocytes → GECs

VEGF-C over-expressed in podocytes; VEGF receptors

VEGF-C/VEGFR signaling pathways

Reducing the loss of GECs fenestrations

[87]

Podocytes → MCs

Podocyte-specific over-expressed VEGF

PDGF-B-mediated signaling pathways

Decreasing MC markers such as α-SMA, desmin, and PDGFR-β significantly

[88]

Podocytes → MCs

VEGF-A over-expressed in podocytes

VEGF-A/VEGFR signaling pathways

Inducing mesangial expansion

[89]

Podocytes → MCs

VEGF-A overexpressed in podocytes

VEGF-A/VEGFR signaling pathways

Maintaining the survival and differentiation of MCs

[90]

Podocytes → GECs

Edn1 secreted by podocytes

Edn1/ Ednra signaling pathways

Destroying endothelial cells by activating oxidative stress

[91]

Podocytes → GECs

Increasing circulating Edn1

Edn1/ Ednra signaling pathways

Inducing endothelial oxidative stress;

Ameliorating mitochondrial ROS in GECs by HG, podocyte loss, albuminuria and glomerulosclerosis

[92]

Podocytes → GECs

Edn1 derived from podocytes;

SUMO-specific peptidase 6

Edn1-mediated crosstalk between podocytes and GECs

Exacerbating podocyte loss and GECs dysfunction by HG

[13]

Podocytes → MCs

Ednra and Ednrb specifically deleted in podocytes

β-catenin and NF-κB signaling pathways mediated by endothelin receptors

Avoiding the podocyte loss; Inhibiting the mesangial expansion

[93]

MCs → podocytes

ERAD-related proteins such as phosphorylated IRE1α, Derlin-1, and Derlin-2

ERAD-related signaling pathway

Causing the aggravation of albuminuria and more podocytes’ apoptosis

[93]

GECs → Podocytes

Pro-apoptotic paracrine signaling factors

Mitochondrial dysfunction and oxidative stress

Increasing podocyte apoptosis, cell shrinkage, and some detachment, the increasing level of caspase 3 and cytosckeleton rearrangement

[94]

GECs → MCs

GECs derived NO

Nitric oxide-mediated signaling pathways

Inducing cGMP formation in MCs in a NO dependent manner, related to the regulation of the intraglomerular capillary flow

[95]

GECs → Podocytes

eNOS derived NO

Nitric oxide-mediated signaling pathways

Supporting podocytes with eNOS derived NO to maintain their structure and function, and loss of GECs provokes NO deficiency that precedes podocyte injury

[96]

GECs → MCs

eNOS which is deficient in diabetes mice

Nitric oxide-mediated signaling pathways

Appearing mesangial lysis and late mesangial dilatation, form nodular or Kimmelstiel-Wilson like lesions which means the development of DKD

[47, 97]

GECs → Podocytes

NO derived from GECs

Nitric oxide-mediated signaling pathways

Maintaining podocyte structure and function

[98]

Podocytes → GECs

HIF-1α and SENP1 in podocytes under the hypoxia condition

HIF-related signaling pathways; VEGF/VEGFR2 signaling

Promoting HIF-1α stabilization and activation by increasing SENP1 expression in podocytes, thereby maintaining the survival of GECs and angiogenesis

[99]

GECs → Podocytes

Heterozygous knockout of KLF2 in endothelial cells

KLF2-related signaling pathways

Causing more proteinuria, more podocyte damage, and elevating the expression of angiogenesis markers

[100]

GECs → Podocytes

Heterozygous knockout of KLF2 in endothelial cells

KLF2-related signaling pathways

Reducing the number of podocytes and the expression of podocyte markers

[101]

GECs → Podocytes

Chronic LSS-dependent mediators released from GECs

ERK5-related pathway

Improving the anticoagulants and anti-inflammatory phenotypes, and directly affecting podocyte function in co-culture

[102]

GECs → Podocytes

RARRES1 overexpression in endothelial cells; receptor tyrosine kinase Axl

NK-κB signaling pathway

Inducing podocyte injury

[103]

GECs → MCs

PDGF-B localizes to the GECs, and PDGFR-β localizes to the MCs

PDGF-B/PDGFR-β signaling pathways

Recruiting MCs into developing glomeruli and promoting the formation of capillary rings

[104, 105]

GECs → MCs

Both up-regulated PDGF-B and PDGFR-β in the histologically early stage of DKD

PDGF-B/PDGFR-β signaling pathways

Promoting DKD by releasing paracrine signaling mediators to cause MCs’ damage

[106, 107]

GECs → MCs

Increasing PDGF-B/PDGFR-β expression under the HG and hypoxia condition

PDGF-B/PDGFR-β signaling pathways

Leading to MCs’ proliferation and mesangial expansion

[108, 109]

Slit2; Transmembrane Roundabout receptor

Slit2-Robo signaling pathways

Regulating axon guidance, ureteric bud branching, and angiogenesis during kidney development, glomerular filtration

[110, 111]

Slit2 and VEGF derived from MCs; Slit2 and Robo1 in GECs

Robo1/PI3K/Akt/VEGF signaling pathways

Participating in GECs proliferation, migration, and tube formation;

Treating abnormal angiogenesis in early DKD through promoting glomerular vascularization

[112]

Podocytes → MCs

BMP4 specifically expressed in podocytes; Smad1 in MCs

BMP4-Smad1 signaling pathways

Regulating the mesangial expansion in DKD, podocyte loss

[113,114,115]