MicroRNAs: new biomarkers and promising therapeutic targets for diabetic kidney disease

Nascimento, Linicene Rosa do; Domingueti, Caroline Pereira

doi:10.1590/2175-8239-JBN-2018-0165

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Brazilian Journal of Nephrology

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Review Articles • J. Bras. Nefrol. 41 (3) • Jul-Sep 2019 • https://doi.org/10.1590/2175-8239-JBN-2018-0165 copy

MicroRNAs: new biomarkers and promising therapeutic targets for diabetic kidney disease

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Diabetic kidney disease (DKD) is a chronic complication of diabetes mellitus associated with significant morbidity and mortality regarded as a global health issue. MicroRNAs - small RNA molecules responsible for the post-transcriptional regulation of gene expression by degradation of messenger RNA or translational repression of protein synthesis - rank among the factors linked to the development and progression of DKD. This study aimed to offer a narrative review on investigations around the use of microRNAs in the diagnosis, monitoring, and treatment of DKD. Various microRNAs are involved in the pathogenesis of DKD, while others have a role in nephroprotection and thus serve as promising therapeutic targets for DKD. Serum and urine microRNAs levels have also been considered in the early diagnosis and monitoring of individuals with DKD, since increases in albuminuria, decreases in the glomerular filtration rate, and progression of DKD have been linked to changes in the levels of some microRNAs.

Keywords:
Diabetic Nephropathies; MicroRNAs; Drug Therapy; Biomarkers; Early Diagnosis; Prognosis

Stage	Description	Glomerular filtration rate (mL/min/1.73m²)
G1	Normal and high GFR^* * In the absence of markers of renal parenchymal injury, stages G1 and G2 are not used for the diagnosis of CKD.	≥ 90
G2	Mild GFR reduction^* * In the absence of markers of renal parenchymal injury, stages G1 and G2 are not used for the diagnosis of CKD.	60-89
G3a	Mild to moderate GFR reduction	43-59
G3b	Moderate to severe GFR reduction	30-44
G4	Severe GFR reduction	15-29
G5	Kidney failure	< 15
Stage	Description	Albumin urinary excretion (mg/g of creatinine or mg/24 hours)
A1	Normal albuminuria	< 30
A2	Moderate to severe albuminuria	≥ 30 e < 300
A3	Severe albuminuria	≥ 300

Author/Year	Patient categorization	Sample type	Study design	Result
Al Kafaji et al., 2016²³23 Al-Kafaji G, Al-Mahroos G, Al-Muhtaresh HA, Skrypnyk C, Sabry MA, Ramadan AR. Decreased expression of circulating microRNA-126 in patients with type 2 diabetic nephropathy: A potential blood-based biomarker. Exp Ther Med 2016;12:815-22.	52 with DM2 & normal albuminuria 29 with DM2 & moderately increased albuminuria 21 with DM2 & severely increased albuminuria	Serum	Cross-sectional	MicroRNA-126 expression levels were lower in patients with moderately increased albuminuria and even lower in patients with severely increased albuminuria in relation to subjects with normal albuminuria.
Argyropoulos et al., 2013²⁴24 Argyropoulos C, Wang K, McClarty, Huang D, Bernardo J, Ellis D, et al. Urinary microRNA profiling in the nephropathy of type 1 diabetes. PLoS One 2013;8:e54662.	10 with DM1 without DKD 10 with DM1 & severely increased albuminuria 10 with DM1 & intermittent moderately increased albuminuria 10 with DM1 & persistent moderately increased albuminuria	Urine	Longitudinal	MicroRNA-323b-5p levels decreased and microRNA-429 levels increased in patients with moderately increased albuminuria, while the levels of microRNA-619; microRNA-486-3p; microRNA-335-5p; microRNA-552; microRNA-1912; microRNA-1224-3p; microRNA-424-5p; microRNA-141-3p; microRNA-29b-1-5p increased and the levels of microRNA-221-3p decreased in patients with severely increased albuminuria.
Argyropoulos et al., 2015²⁵25 Argyropoulos C, Wang K, Bernardo J, Ellis D, Orchard T, Galas D, et al. Urinary MicroRNA Profiling Predicts the Development of Microalbuminuria in Patients with Type 1 Diabetes. J Clin Med 2015;4:1498-517.	27 with DM1 & normal albuminuria (10 did not develop DKD & 17 developed moderately increased albuminuria)	Urine	Longitudinal	Increased expression levels of microRNA-495; microRNA-548o-3p; microRNA-7a-5p; microRNA-1247-5p; microRNA-767-3p; microRNA-122-5p; microRNA-645; microRNA-199a-5p; microRNA-7b-3p; microRNA-30a-5p; microRNA-17-5p; microRNA-126-3p; microRNA-548c-3p; microRNA-665; microRNA-640; microRNA-302a-3p; microRNA-616-5p; microRNA-770-5p was associated with moderately increased albuminuria, while expression of microRNA-10; microRNA-23; microRNA-30; microRNA-200 was associated with non-development of DKD.
Barutta et al., 2013²⁶26 Barutta F, Tricarico M, Corbelli A, Annaratone L, Pinach S, Grimaldi S, et al. Urinary exosomal microRNAs in incipient diabetic nephropathy. PLoS One 2013;8:e73798.	12 with DM1 & normal albuminuria 12 with DM1 & moderately increased albuminuria	Urine	Cross-sectional	Expression levels of microRNA-130a & microRNA-145 were higher and expression levels of microRNA-155 & microRNA-424 were lower in patients with moderately increased albuminuria in relation to normal albuminuria.
Barutta et al., 2016²⁷27 Barutta F, Bruno G, Matullo G, Chatuverdi N, Grimaldi S, Schalkwijk C, et al. MicroRNA-126 and micro-/macrovascular complications of type 1 diabetes in the EURODIAB Prospective Complications Study. Acta Diabetol 2017;54:133-9.	179 with DM1 & increased albuminuria 143 with DM1 and without DKD	Serum	Cross-sectional	MicroRNA-126 levels were lower in patients with increased albuminuria in relation to controls.
Bijkerk et al., 2015²⁸28 Bijkerk R, Duijs JM, Khairoun M, Ter Horst CJ, Van der Pol P, Mallat MJ, et al. Circulating microRNAs associate with diabetic nephropathy and systemic microvascular damage and normalize after simultaneous pancreas kidney transplantation. Am J Transplant 2015;15:1081-90.	21 with DM1 & GFR < 30 mL/min 15 with DM1 & GFR ≥ 30 mL/min	Serum	Cross-sectional	MicroRNA181a & microRNA-326 levels were increased and microRNA-126 & microRNA-574-3p levels were decreased in patients with GFR < 30 mL/min in relation to patients with GFR ≥ 30 mL/min.
Wang et al., 2016²⁹29 Wang C, Wan S, Yang T, Niu D, Zhang A, Yang C, et al. Increased serum microRNAs are closely associated with the presence of microvascular complications in type 2 diabetes mellitus. Sci Rep 2016;6:20032.	92 with DM2 & microvascular complications 92 with DM2 without complications	Serum	Cross-sectional	The levels of microRNA-661; microRNA-571; microRNA-770-5p; microRNA-892b; microRNA-1303 were increased in patients with microvascular complications in relation to patients without complications.
El-Samahy et al., 2018³⁰30 El-Samahy MH, Adly AA, Elhenawy YI, Ismail EA, Pessar SA, Mowafy ME, et al. Urinary miRNA-377 and miRNA-216a as biomarkers of nephropathy and subclinical atherosclerotic risk in pediatric patients with type 1 diabetes. J Diabetes Complications 2018;32:185-92.	26 with DM1 & normal albuminuria 24 with DM1 & increased albuminuria	Urine	Cross-sectional	MicroRNA-377 levels were increased and microRNA-216a levels were decreased in patients with increased albuminuria in relation to patients with normal albuminuria.

MicroRNAs with decreased expression levels	Reference
microRNA-126	Al Kafaji et al., 2016²³23 Al-Kafaji G, Al-Mahroos G, Al-Muhtaresh HA, Skrypnyk C, Sabry MA, Ramadan AR. Decreased expression of circulating microRNA-126 in patients with type 2 diabetic nephropathy: A potential blood-based biomarker. Exp Ther Med 2016;12:815-22.
microRNA-221-3p; microRNA-323b-5p	Argyropoulos et al., 2013²⁴24 Argyropoulos C, Wang K, McClarty, Huang D, Bernardo J, Ellis D, et al. Urinary microRNA profiling in the nephropathy of type 1 diabetes. PLoS One 2013;8:e54662.
microRNA-10; microRNA-23; microRNA-30; microRNA-200	Argyropoulos et al., 2015²⁵25 Argyropoulos C, Wang K, Bernardo J, Ellis D, Orchard T, Galas D, et al. Urinary MicroRNA Profiling Predicts the Development of Microalbuminuria in Patients with Type 1 Diabetes. J Clin Med 2015;4:1498-517.
microRNA-155; microRNA-424	Barutta et al., 2013²⁶26 Barutta F, Tricarico M, Corbelli A, Annaratone L, Pinach S, Grimaldi S, et al. Urinary exosomal microRNAs in incipient diabetic nephropathy. PLoS One 2013;8:e73798.
microRNA-126	Barutta et al., 2016²⁷27 Barutta F, Bruno G, Matullo G, Chatuverdi N, Grimaldi S, Schalkwijk C, et al. MicroRNA-126 and micro-/macrovascular complications of type 1 diabetes in the EURODIAB Prospective Complications Study. Acta Diabetol 2017;54:133-9.
microRNA-126; microRNA-574-3p	Bijkerk et al., 2015²⁸28 Bijkerk R, Duijs JM, Khairoun M, Ter Horst CJ, Van der Pol P, Mallat MJ, et al. Circulating microRNAs associate with diabetic nephropathy and systemic microvascular damage and normalize after simultaneous pancreas kidney transplantation. Am J Transplant 2015;15:1081-90.
microRNA-216a	El-Samahy et al., 2018³⁰30 El-Samahy MH, Adly AA, Elhenawy YI, Ismail EA, Pessar SA, Mowafy ME, et al. Urinary miRNA-377 and miRNA-216a as biomarkers of nephropathy and subclinical atherosclerotic risk in pediatric patients with type 1 diabetes. J Diabetes Complications 2018;32:185-92.
MicroRNAs with increased expression levels	Reference
microRNA-29b-1-5p; microRNA-141-3p; microRNA-335-5p; microRNA-424-5p; microRNA-429; microRNA-486-3p; microRNA-552; microRNA-619; microRNA-1224-3p; microRNA-1912	Argyropoulos et al., 2013²⁴24 Argyropoulos C, Wang K, McClarty, Huang D, Bernardo J, Ellis D, et al. Urinary microRNA profiling in the nephropathy of type 1 diabetes. PLoS One 2013;8:e54662.
microRNA-7a-5p; microRNA-7b-3p; microRNA-17-5p; microRNA-30a-5p; microRNA-122-5p; microRNA-126-3p; microRNA-199a-5p; microRNA-302a-3p; microRNA-495; microRNA-548c-3p; microRNA-548o-3p; microRNA-616-5p; microRNA-640; microRNA-645; microRNA-665; microRNA-767-3p; microRNA-770-5p; microRNA-1247-5p	Argyropoulos et al., 2015²⁵25 Argyropoulos C, Wang K, Bernardo J, Ellis D, Orchard T, Galas D, et al. Urinary MicroRNA Profiling Predicts the Development of Microalbuminuria in Patients with Type 1 Diabetes. J Clin Med 2015;4:1498-517.
microRNA-130a; microRNA-145	Barutta et al., 2013²⁶26 Barutta F, Tricarico M, Corbelli A, Annaratone L, Pinach S, Grimaldi S, et al. Urinary exosomal microRNAs in incipient diabetic nephropathy. PLoS One 2013;8:e73798.
microRNA181a; microRNA-326	Bijkerk et al., 2015²⁸28 Bijkerk R, Duijs JM, Khairoun M, Ter Horst CJ, Van der Pol P, Mallat MJ, et al. Circulating microRNAs associate with diabetic nephropathy and systemic microvascular damage and normalize after simultaneous pancreas kidney transplantation. Am J Transplant 2015;15:1081-90.
microRNA-571; microRNA-661; microRNA-770-5p; microRNA-892b; microRNA-1303	Wang et al., 2016²⁹29 Wang C, Wan S, Yang T, Niu D, Zhang A, Yang C, et al. Increased serum microRNAs are closely associated with the presence of microvascular complications in type 2 diabetes mellitus. Sci Rep 2016;6:20032.
microRNA-377	El-Samahy et al., 2018³⁰30 El-Samahy MH, Adly AA, Elhenawy YI, Ismail EA, Pessar SA, Mowafy ME, et al. Urinary miRNA-377 and miRNA-216a as biomarkers of nephropathy and subclinical atherosclerotic risk in pediatric patients with type 1 diabetes. J Diabetes Complications 2018;32:185-92.

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[1] Correspondence to: Caroline Pereira Domingueti. E-mail: caroldomingueti@ufsj.edu.br