TABLE 2.
Top 10 cell‐type‐enriched EV mRNA also detected in human urinary extracellular vesicles
| Gene name | description | Function | Association with diseases | References | Open targets | IPA |
|---|---|---|---|---|---|---|
| Podocytes | ||||||
| PLEKHB2 | pleckstrin homology domain containing B2/evectin‐2 | Involved in retrograde transport of recycling endosomes. | Role in proliferation of metastatic cells by activating Yes‐associated protein in cardiomyocytes. | (Matsudaira et al., 2017) | yes | |
| COBLL1 | cordon‐bleu WH2 repeat protein like 1 | Associated with prostate cancer progression. It stimulates androgen receptor signalling pathway and modulates the cell morphology. Also, its upregulation is associated with chronic lymphocytic leukaemia reduced survival. Associated with apoptosis and fibrosis in cardiomyoblasts. | (Plešingerová et al., 2018; Takayama et al., 2018; Xiong et al., 2021) | no | ||
| MRPL57 | mitochondrial ribosomal protein L57 | Component of the mitochondrial large ribosomal subunit. | no | |||
| LCP1 | lymphocyte cytosolic protein 1 | Actin‐binding protein. | Downregulation reduces motility and proliferation of breast cancer cells in vitro and in a mouse model. Involved in Hypereosinophilia by activating mTORC2/Akt. Candidate circulating biomarker for kidney cancer. | (Ma et al., 2020; Pillar et al., 2019; Su Kim et al., 2013), | yes | Renal cancer |
| GNG4 | G protein subunit gamma 4 | Subunit required for the guanine nucleotide‐binding proteins GTPase activity, for replacement of GDP by GTP, and for G protein‐effector interaction. | Upregulated in liver cancer, promotes cell proliferation and adhesion. Downregulation in colon cancer cells reduced proliferation and migration and invasion. Association with cognitive decline as a consequence of aging. | (Bonham et al., 2018; Liang et al., 2021; Tanaka et al., 2021) | yes | |
| WSB1 | WD repeat and SOCS box containing 1 | Probable substrate‐recognition component of a SCF‐like ECS (Elongin‐Cullin‐SOCS‐box protein) E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. | In cancer, WSB1 upregulates hypoxia inducible factors by pVHL ubiquitination and proteosomal degradation. It is also associated with thyroid hormone homeostasis and immune regulation. | (Haque et al., 2016; Kim et al., 2015) | yes | |
| ALDH6A1 | aldehyde dehydrogenase 6 family member A1 | Plays a role in the valine and pyrimidine catabolic pathways. | Downregulation in renal cell carcinoma which was associated with poor survival. Also survival predictive value for metastatic prostate cancer. | (Cho et al., 2018; Lu et al., 2020) | yes | |
| ORC4 | origin recognition complex subunit 4 | Subunit of the ORC, which is essential for the initiation of the DNA replication in eukaryotic cells. | Postulated as a gene which could be involved in eGFR for kidney disease of diverse origin. | (Morris et al., 2019) | yes | |
| STYXL1 | serine/threonine/tyrosine interacting like 1 | STYXL1 is an inactive phosphatase. It binds to G3BP1 and inhibits the formation of G3BP1‐induced stress granules. | Upregulated in glioma and hepatocellular carcinoma. Upregulation is associated with poor prognosis | (Tomar et al., 2019; J. Z. Wu, Jiang, Lin & Liu, 2020) | yes | Renal clear cell adenocarcinoma |
| MESANGIAL CELLS | ||||||
| KRT19 | keratin 19 | Intermediate filament Involved in the organisation of myofibers. | Associated with increased risk of developing tumours in kidney failure. Upregulated in diverse models of tubular injury. High expression in breast and thyroid cancer. | (Djudjaj et al., 2016; Martínez‐Camberos et al., 2022; Sarlos et al., 2018) | yes | Autosomal dominant polycystic kidney disease |
| TXNIP | thioredoxin interacting protein | Protects cells from oxidative stress by regulating of cellular redux status. | Role in kidney fibrosis related to aging. Upregulated by hyperglycaemia in kidney. Knock‐out attenuates DKD histopathological changes in a streptozotocin model of diabetes. | (De Marinis et al., 2016; Shah et al., 2015) | yes | Oxidative stress response, damage of renal glomerulus, failure of kidney, injury of podocytes |
| MT‐ND2 | mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 2 | Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I). | Associates with higher risk to develop nephropathy in T2D. Mutations associated with maternal transmitted T2D. | (Jiang et al., 2021; X. Yang, Zhang, Ma, Zhao & Lyu, 2015) | yes | |
| MT‐ND1 | mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1 | Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) | Mutations associated with maternal transmitted T2D. In colorectal cancer, circulating levels are associated with progression and response to chemotherapy. | (Jiang et al., 2021) | yes | Chromophobe renal cell carcinoma |
| PABPC1 | poly(A) binding protein cytoplasmic 1 | PABPC1 binding to poly(A) promotes ribosome recruitment and translation initiation. It is also involved in poly(A) shortening. | Upregulated in oesophageal squamous cell carcinoma, which promotes angiogenesis and malignant progression. Upregulated in gastric cancer and hepatocellular carcinoma where can act as a prognostic biomarker. Mutations of these genes were found in renal cancers. | (An et al., 2021; Yamamoto et al., 2021; YuFeng & Ming, 2020; Y. Zhang et al., 2022) | yes | Renal cancer |
| S100A11 | S100 calcium binding protein A11 | It may play a role in cell motility, invasion and tubulin polymerisation | level of expression in primary clear cell renal cell carcinoma can predict disease free survival. Regulates cell proliferation, invasion and migration in renal cell carcinoma through EGFR/Akt. | (Gabril et al., 2016; Liu et al., 2017) | yes | Renal cell carcinoma |
| RPS27A | ribosomal protein S27a | Part od the 40s ribosomal subunit | Associated with cervical cancer prognosis. In in lung adenocarcinoma cells regulates apoptosis, proliferation and cell cycle. It may control microglia activation in neurodegenerative diseases. | (Khayer et al., 2020; Li et al., 2022; Wang et al., 2021) | yes | |
| ATP5F1A | ATP synthase F1 subunit alpha, mitochondrial | Subunit of mitochondrial ATP synthase | In HeLa cells, overexpression of ATP5F1A regulated the expression of genes related to innate immune response, angiogenesis and collagen catabolic processed. It also regulated the alternative splicing of genes involved in glucose homeostasis. Associated with clear cell renal cell carcinoma prognosis. | (Song et al., 2021; Yuan et al., 2018) | yes | |
| CNDP2 | carnosine dipeptidase 2 | It is a nonspecific dipeptidase, hydrolyses a variety of dipeptides including L‐carnosine | Variants of these genes are associated with risk of kidney disease in T2D. Upregulated in substantia nigra pars compacta during Parkinson disease. Role in cancer growth and metastasis of ovarian cancer. | (Ahluwalia et al., 2011; Licker et al., 2012; Zhang et al., 2019) | yes | |
| SKP1 | S‐phase kinase associated protein 1 | Component of the SCF complexes, participates in ubiquitination of specific protein substrates for their degradation at the proteosome. | Role in colon cancer cell proliferation. Role in the progression of hepatocellular carcinoma. | (Zhai et al., 2017; Zhu et al., 2021) | yes | |
| Proximal tubule cells | ||||||
| GPX3 | glutathione peroxidase 3 | It protects cells against oxidative damage by catalysing the reduction of organic hydroperoxides and hydrogen peroxide by glutathione. | Downregulated in a mouse model of DN. Associated with cardiac disease. Acts as a tumour suppressor in kidney cell lines | (An et al., 2018; Morito et al., 2014; Pang et al., 2018) | yes | Chromophobe renal cell carcinoma, papillary renal cell carcinoma |
| ASCC2 | activating signal cointegrator 1 complex subunit 2 | As part of the ASCC complex, it is involved in DNA damage repair. As part of the ASC‐1 complex plays a role enhancing NF‐kappa‐B, SRF and AP1 transactivation. | Associated with coronary artery disease. In cancer, somatic mutations interferes with ASCC2‐ASCC3 interaction, which disturbs DNA repair. | (Jia et al., 2020; Y. Yang & Xu, 2021) | yes | |
| B2M | beta‐2‐microglobulin | Component of the class I major histocompatibility complex. | Associated with acute kidney injury severity. Indicator of tubular injury and glomerular filtration. | (Barton et al., 2018; Grubb et al., 1985) | yes | Acute kidney injury, acute renal allograft rejection, DN, ostertag type, injury of renal glomerulus |
| DAP | death associated protein | Dap is a positive regulator of apoptosis induced by interferon‐gamma and a negative regulator of autophagy. | In breast cancer, role in cell migration, proliferation and adhesion. | (Wazir et al., 2015) | yes | |
| MARCKSL1 | Myristoylated alanine‐rich C kinase substrate‐like 1 | It plays a role in the formation of adherens function. It controls cell movement through the regulation of cytoskeleton homeostasis. | Downregulated in DN. Anti‐angiogenic function preventing the VEGF phosphorylation mediated by Akt/PDK‐1/mTOR pathway. | (Kim et al., 2016; Tang et al., 2020) | yes | |
| BASP1 | brain abundant membrane attached signal protein 1 | Membrane bound protein with several transient phosphorylation sites and PEST motifs. PEST motif is associated with proteins that have a short intracellular half‐life. | Mediates albumin induced apoptosis in tubular cells. In podocytes, pro‐apoptotic in DN. | (Sanchez‐Niño et al., 2010; Zhang et al., 2021) | yes | Renal cell carcinoma |
| OSBP | oxysterol binding protein | It is a lipid transporter which delivers sterol to the Golgi in exchange for PI4P to the endoplasmic reticulum. It is also believed to transport sterols from lysosomes to the nucleus. | Plays a role in insulin granule formation in rat insulinoma cell line. Role in regulating the proatherogenic protein profilin‐1 under diabetic like conditions. | (Hussain et al., 2018; Romeo & Kazlauskas, 2008) | yes | |
| LMNA | lamin A/C | Component of the nuclear lamina. | Some variants are associated to cardiac disease. Mutation of these gene is associated with proteinuric renal disease and membranous glomerulonephritis. | (Fountas et al., 2017; Fujita & Hatta, 2018; Lazarte et al., 2022) | yes | Renal clear cell adenocarcinoma |
| PDLIM5 | PDZ and LIM domain 5 | It binds protein kinases to the Z‐disk in striated muscles. It may have a role in cardiomyocyte expansion and in preventing postsynaptic growth of excitatory synapses. | Recruited to integrin adhesion complexes in Podocyte. Polymorphisms of this gene are associated with T2D and hypertension. | (Maier et al., 2021; Owusu et al., 2017) | yes | |
| STARD10 | StAR related lipid transfer domain containing 10 | The protein encoded by this gene transfer phospholipids. It can transfer phosphatidylcholine and phosphatidylethanolamine between membranes. | Deletion of STARD10 impairs insulin secretion. Upregulated in breast cancer. | (Carrat et al., 2017; Olayioye et al., 2004) | yes | |
| Glomerular endothelial cells | ||||||
| TMSB4X | thymosin beta 4 X‐linked | Actin sequestering protein that inhibits actin polymerisation. It is also involved in cell proliferation, migration and differentiation. | Reduces lung inflammation and fibrosis induced by LPS. Administration of TMSB4X reduced the kidney damage in a model od DN. | (Tian et al., 2022; Zhu et al., 2015) | yes | |
| FDFT1 | farnesyl‐diphosphate farnesyltransferase 1 | Role in cholesterol biosynthesis. Enzyme that catalyses the dimerisation of 2 farnesyl pyrophosphate groups to form squalene. | Antitumoral effect by inhibiting AKT/mTOR/HIF1α pathway during fasting in colorectal cancer. Associated with fibrosis progression in chronic hepatitis C. | (Stättermayer et al., 2014; Weng et al., 2020) | yes | Cell death of kidney cell lines, metastatic renal cancer, renal cell carcinoma, renal osteodystrophy |
| SELENOW | selenoprotein W | It plays a role as a glutathione‐dependent antioxidant and may have a redox function | During nervous system development, it Protects neurons against oxidative stress. | (Chung et al., 2009) | yes | Adhesion of multiple myeloma endothelial cells |
| SNCG | synuclein gamma | It plays a role in neurofilament network integrity and may modulate the keratin network in skin | Protection against ER stress by regulating autophagy in colon cancer cells. Promotes cancer metastasis. Downregulation in endometrial cancer cells prevented proliferation, migration and invasion, and promoted apoptosis. | (Liu et al., 2022; Ni et al., 2021; Ye et al., 2021) | yes | |
| GLUL | glutamate‐ammonia ligase | It is involved in ammonia and glutamate detoxification, acid‐base homeostasis, cell signalling and cell proliferation. | In early DN, GLUL is downregulated in podocytes. Associated with cardiovascular disease in T2D. | (Look AHEAD Research Group, 2016; Wei et al., 2021) | yes | Early stage DN, migration of endothelial cells, migration of vascular endothelial cells, sprouting of vascular endothelial cells |
| ARHGDIB | Rho GDP dissociation inhibitor beta | Regulates the GDP/GTP exchange reaction of the Rho proteins by inhibiting the dissociation of GDP from them, and the subsequent binding of GTP to them. | Development of antibodies against ARHGDIB protein are associated with kidney graft loss. Upregulated in breast cancer and associated with prognosis. | (Kamburova et al., 2019; Wang et al., 2020) | yes | |
| GTF3A | general transcription factor IIIA | It is involved in ribosomal large subunit biogenesis. | Dysregulated in secondary hyperparathyroidism. | (Santamarea et al., 2005) | yes | |
| CALCOCO2 | calcium binding and coiled‐coil domain 2 | It acts as a receptor for ubiquitin‐coated bacteria and plays and a role in innate immunity by mediating macroautophagy. | Dysregulated in dilated cardiomyopathy with increased autophagy. Role in mitophagy. | (Gil‐Cayuela et al., 2019; Yamano & Youle, 2020) | no | |
| RBM3 | RNA binding motif protein 3 | It enhances global protein synthesis. It is Induced by cold shock and low oxygen tension. | Role in inducing the proliferation of hepatocellular carcinoma. In hypoxic conditions, promotes neural stem cells proliferation. | (Miao & Zhang, 2020; Yan et al., 2019) | yes | Renal cancer |
| TCEAL4 | transcription elongation factor A like 4 | Involved in transcription modulation in a promoter context‐dependent manner. | Downregulated in gestational diabetes. Down regulated in anaplastic thyroid cancer. | (Akaishi et al., 2006; Alur et al., 2021) | yes | Renal clear cell adenocarcinoma |
Note: Top 10 mRNAs were selected based on their level of expression in urinary extracellular vesicles dataset. Functions (as reported in uniprot, humanmine and bibliography) and examples of association to kidney disease and/or other diseases (evaluated using open targets kidney disease entries, ingenuity pathway analysis (IPA) and bibliography).
Abbreviations: AP1, activator protein 1; ASC1, activating signal cointegrator 1 complex; BAX, Bcl‐2‐associated X; BCL‐2, B‐cell lymphoma 2; DN, diabetic nephropathy; EGFR, epidermal growth facrtor receptor; eGFR, estimated glomerular filtration rate; G3BP1, Ras GTPase‐activating protein‐binding protein 1; GDP, guanosine diphosphate; GTP, guanosine triphosphate; JAK, Janus kinases; mTOR, mammalian target of rapamycin; mTORC2, mammalian target of rapamycin complex 2; NADH, reduced nicotinamide adenine dinucleotide; NF‐kappa‐B, nuclear factor kappa beta; ORC, origin recognition complex; PDK‐1, 3‐phosphoinositide dependent protein kinase 1; PEST motif, Proline, glutamic acid, serine and threonine; PI3K, phosphoinositide 3‐kinase; PI4P, phosphatidylinositol‐4‐phosphate; PTEN, phosphatase and tensin homolog; SCF complex, Skp, Cullin, F‐box containing complex; SRF, serum response factor; STAT3, signal transducer and activator of transcription protein 3; T2D, type 2 diabetes; VEGF, vascular endothelial growth factor.