Employing extracellular vesicles for non-invasive renal monitoring: A captivating prospect

Table 2 Putative disease-associated protein and RNA biomarkers identified in urinary extracellular vesicles

Name of the putative marker	UniProt ID/RNA name	Molecular and biological function	Associated Kidney disease(s )	Disease/model	Ref.
Adenine phosphoribosyltransferase	APT_HUMAN	Enzyme involved in the purine nucleotide salvage pathway. Its deficiency can lead to urolithiasis and renal failure	APRT deficiency	Healthy	[62]
Low-density lipoprotein receptor- related protein 2 mRNA	LRP2_HUMAN (megalin), LRP2	Multi-ligand binding receptor; mediates endocytic uptake of complexes between the steroid 25(OH) vitamin D3 and vitamin D-binding protein in kidney proximal tubules	Donnai-Barrow syndrome; Renal aminoglycoside accumulation; Nephrotoxicity	Healthy	[38,78]
Polycystin-1, Polycystin-2	PKD1_HUMAN PKD2_HUMAN	Integral membrane glycoproteins, associated with structural and/or functional defects in the primary apical cilium of epithelia and polycystic kidney disease	ADPKD	Healthy	[45,46,54,62]
Solute carrier family 12 member 2 (Sodium potassium chloride cotransporter-2)	S12A2_HUMAN	Membrane transporter: aids in the active transport of sodium, potassium, and chloride into and out of cells; NKCC2 mutations lead to type I Bartter syndrome	Antenatal Bartter syndrome type 1	Healthy	[33,41,62]
Myosin-9	MYH9_HUMAN	MYH9 polymorphisms have been shown to associate with glomerulosclerosis and non-diabetic end stage renal disease	Fechtner syndrome and Epstein syndrome	Healthy	[62]
Aquaporin-2 mRNA	AQP2_HUMAN AQP2	Molecular water channel in the basolateral and apical plasma membranes of the collecting duct	Autosomal dominant and autosomal recessive nephrogenic diabetes insipidus	Healthy; Various kidney diseases	[24,33,38,39,44 ,54,58,62,95]
Neprilysin (CD10)	NEP_HUMAN	Surface metallo-endopeptidase highly expressed in the kidney brush-border membranes	Membranous glomerulonephritis	Healthy; Diabetic nephropathy, Renal cell carcinoma	[25,33,77,95]
Osteoprotegerin	TR11B_HUMAN	Decoy receptor of proximal tubular cells	chronic kidney disease-mineral and bone disorder	Healthy; ADPKD CKDD patients	[49]
Podocalyxin	PODXL_HUMAN	he major sialoprotein of kidney glomerulus; Involved in the regulation of cell adhesion, cell morphology and cancer progression	Autosomal recessive steroid–resistant nephrotic syndrome	Healthy; Glomerular disease; Renal cell carcinoma	[42,58,62,77,95]
Solute carrier family 12 member 3 (Thiazide- sensitive Na-Cl cotransporter; NCC)	S12A3_HUMAN	Membrane transporter highly expressed in the kidney: aids reabsorbing sodium and chloride ions from the tubular fluid into the cells of the distal convoluted tubule of the nephron	Gitelman syndrome; Aldosteronism	Healthy; High blood pressure; Aldosteronism	[41,62,79]
Protein AMBP (alpha-1-microglobulin; bikunin precursor)	AMBP_HUMAN	Membrane glycoprotein with serine protease inhibitor activity	Diabetic nephropathy	Healthy; DN patients in advanced disease stages	[16,45]
Leucine-rich alpha-2-glycoprotein-1	LRG1_HUMAN	Involved in protein-protein interaction, signal transduction, and cell adhesion and development; Expressed during granulocyte differentiation	NSCLC	Healthy; NSCLC	[71]
Matrix metalloproteinase 9	MMP9_HUMAN	Involved in extracellular matrix remodeling	Renal cell carcinoma	Healthy; Renal cell carcinoma	[77]
Basigin , Extracellular Matrix Metallo- proteinase Inducer	BASI_HUMAN	Involved in extracellular matrix remodeling	Renal cell carcinoma	Healthy; Renal cell carcinoma	[77]
Ceruloplasmin	CERU_HUMAN	A ferroxidase enzyme in serum	Renal cell carcinoma	Healthy; Renal cell carcinoma	[77]
Dickkopf related protein 4	DKK4_HUMAN	Involved in extracellular matrix remodeling	Renal cell carcinoma	Healthy; Renal cell carcinoma	[77]
Carbonic Anhydrase 9	CAH9_HUMAN	A metalloenzyme that catalyzes the reversible hydration of carbon dioxide	Renal cell carcinoma	Healthy; Renal cell carcinoma	[77]
Dipeptidase 1	DPEP1_HUMAN	A kidney membrane enzyme that hydrolyzes a variety of dipeptides and is implicated in renal metabolism of glutathione and its conjugates	Renal cell carcinoma	Healthy; Renal cell carcinoma	[77]
Syntenin-1	SDCB1_HUMAN	Scaffold protein Pbp1 Syndecan-binding protein	Renal cell carcinoma	Healthy; Renal cell carcinoma	[77]
Leucine-rich repeatkinase2	LRRK2	A member of the leucine-rich repeat kinase family; Associated to risks to inflammation-linked diseases that include Crohn’s disease and mycobacterium infection	Parkinson’s disease	Healthy; Parkinson’s disease	[50]
Activating transcription factor 3	ATF3_HUMAN miRNA494	Transcription factor with protective role in renal ischemia-reperfusion injury	AKI	AKI	[22]
Fetuin-A	FETUA_HUMAN	Plasma binding glycoprotein; inhibitor of calcification, regulator of cell-dependent process of osteogenesis	AKI	AKI	[46,96]
Wilm’s tumor protein	WT1_HUMAN	Zinc finger protein with essential role in the normal development of the urogenital system	Early podocyte injury in diabetic nephropathy; steroid responsiveness or renal pathological conditions in patients with idiopathic nephrotic syndrome	FSGS patients; Diabetic Patients with or without Proteinuria; idiopathic nephrotic syndrome	[22,30,92]
Isoform 1 of histone-lysine N-methyltransferase	MLL3_HUMAN	Histonemethyltransferase which methyl- ates “Lys-4” of histone H3, a specific tag for epigenetic transcriptional activation	Diabetic nephropathy	DN patients in advanced disease stages	[16]
Voltage-dependent anion-selective channel protein 1	VDAC1_HUMAN	Porin ion channel of the outer mitochondrial membrane	Diabetic nephropathy	DN patients in advanced disease stages	[16]
GPRC5B	GPC5B_HUMAN	G protein coupled receptor required for tubulogenesis	Acute Kidney Disease	AKD	[94]
Aquaporin-1 mRNA	AQP1_HUMAN AQP1	Molecular water channel in the basolateral and apical plasma membranes of the proximal tubules.	Renal ischaemia reperfusion injury	Renal transplantation; Renal cell carcinoma	[38,77,97]
Neutrophil gelatinase-associated lipocalin	NGAL_HUMAN	Iron-trafficking protein involved in multiple processes such as apoptosis, innate immunity and renal development. In the kidney it is produced by distal nephron	kidney transplantation	kidney allograft recipients	[91]
Immunoglobulin light chain	IGLL1_HUMAN IGKC_HUMAN	Immunoglobulin light chain is the small polypeptide subunit of an antibody	Light Chain Amyloidosis	Light chain amyloidosis; multiple myeloma; monoclonal gammopathy; non-paraproteinemia related kidney disease	[65]
Panel of 24 proteins _HUMAN	SERPINA1, A2M, APOA1, APOA2, CA1, CD5L, DPEP1, FGA, FGB, FGG, FN1, GSTT1, SLC2A1, HBA1, HBB, SERPIND1, HP, HPR, ITIH1, PON1, RAB27B, S100A8, S100A9, TACSTD2	-	Bladder cancer	Bladder cancer; Hernia	[77]
PSA	KLK3_HUMAN	Serine protease with diverse physiological functions; implicated in carcinogenesis	Prostate cancer	Prostate cancer	[56]
Glutamate carboxypeptidase 2 (Prostate-specific membrane antigen-PSMA)	FOLH1_HUMAN	Folate hydrolase and N-acetylated-alpha-linked-acidic dipeptidase activity; Involved in prostate tumor progression	Prostate cancer	Prostate cancer	[56]
microRNA	MicroRNA-29c	-	Renal fibrosis	Healthy; CKD	[40]
microRNA	miR-130A	-	Type 1 diabetes	type 1 diabetic patients with and without incipient diabetic nephropathy	[81]
microRNA	miR-145	-	Type 1 diabetes	type 1 diabetic patients with and without incipient diabetic nephropathy	[81]
microRNA	miR-155	-	Type 1 diabetes	type 1 diabetic patients with and without incipient diabetic nephropathy	[81]
microRNA	miR-424	-	Type 1 diabetes	type 1 diabetic patients with and without incipient diabetic nephropathy	[81]
mRNA (CD2-associated protein)	CD2AP	-	Podocyte injury	Healthy; diabetic nephropathy; focal segmental glomerulosclerosis; IgA nephropathy;membranous nephropathy	[39]
mRNA (Prostate cancer antigen 3)	PCA-3	-	Prostate cancer	Healthy; Prostate cancer	[32]
mRNA (TMPRSS2/ERGa fusion transcript)	TMPRSS2:ERG	-	Prostate cancer	Healthy; Prostate cancer	[32]

CKD: Chronic kidney disease; AKI: Acute kidney injury; PSA: Prostate specific antigen; NSCLC: Non-small cell lung cancer; APRT: Adenine phosphoribosyltransferase deficiency; CD2AP: CD2-associated protein; PCA-3: Prostate cancer antigen 3; ADPKD: Autosomal dominant polycystic kidney disease.