Int J Med Sci 2021; 18(10):2093-2101. doi:10.7150/ijms.56551 This issue

Research Paper

Long noncoding RNAs may impact podocytes and proximal tubule function through modulating miRNAs expression in Early Diabetic Kidney Disease of Type 2 Diabetes Mellitus patients

Ligia Petrica1,2,8,10*, Elena Hogea3*, Florica Gadalean1,2✉, Adrian Vlad2,4, Mihaela Vlad2,5, Victor Dumitrascu2,6, Silvia Velciov1,2, Cristina Gluhovschi1,2, Flaviu Bob1,2, Sorin Ursoniu2,7,8,10, Dragos Catalin Jianu2,9,10, Petru Matusz11, Agneta-Maria Pusztai11, Andrei Motoc11, Octavian M Cretu12, Dana Radu13, Oana Milas1,2, Alina Golea-Secara1,2, Anca Simulescu1,2, Maria Mogos-Stefan1,2, Mihaela Patruica1,2, Lavinia Balint1,2, Silvia Ienciu1,2, Daliborca Vlad2,6#, Roxana Popescu2,14#

1. Dept. of Internal Medicine II - Division of Nephrology, “Victor Babes” University of Medicine and Pharmacy Timisoara, Romania, Eftimie Murgu Sq. no. 2, 300041 Timisoara, RO; County Emergency Hospital Timisoara, RO.
2. Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania Eftimie Murgu Sq. no. 2, 300041 Timisoara, RO.
3. Department of Microbiology XIV- Division of Microbiology-Virusology, ”Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania, Eftimie Murgu Sq. no. 2, 300041 Timisoara, RO.
4. Dept. of Internal Medicine II - Division of Diabetes and Metabolic Diseases, “Victor Babes” University of Medicine and Pharmacy Timisoara, Romania, Eftimie Murgu Sq. no. 2, 300041 Timisoara, RO; County Emergency Hospital Timisoara, RO.
5. Dept. of Internal Medicine II - Division of Endocrinology, “Victor Babes” University of Medicine and Pharmacy Timisoara, Romania, Eftimie Murgu Sq. no. 2, 300041 Timisoara, RO; County Emergency Hospital Timisoara, RO.
6. Dept. of Biochemistry and Pharmacology - Division of Pharmacology, “Victor Babes” University of Medicine and Pharmacy Timisoara, Romania, Eftimie Murgu Sq. no. 2, 300041 Timisoara, RO; County Emergency Hospital Timisoara, RO.
7. Dept. of Functional Sciences - Division of Public Health Medicine, Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania, Eftimie Murgu Sq. no. 2, 300041 Timisoara, RO; County Emergency Hospital Timisoara, RO.
8. Center for Translational Research and Systems Medicine, Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania, Eftimie Murgu Sq. no. 2, 300041 Timisoara, RO.
9. Dept. of Neurosciences - Division of Neurology, “Victor Babes” University of Medicine and Pharmacy Timisoara, Romania; Eftimie Murgu Sq. no. 2, 300041 Timisoara, RO; County Emergency Hospital Timisoara, RO.
10. Centre for Cognitive Research in Neuropsychiatric Pathology (Neuropsy-Cog), Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania, Eftimie Murgu Sq. no. 2, 300041 Timisoara, RO.
11. Dept. of Anatomy and Embryology- Division of Anatomy and Embryology; “Victor Babes” University of Medicine and Pharmacy Timisoara, Romania; Eftimie Murgu Sq. no. 2, 300041 Timisoara, RO.
12. Dept. of Surgery I- Division of Surgical Semiology I, “Victor Babes” University of Medicine and Pharmacy Timisoara, Romania; Eftimie Murgu Sq. no. 2, 300041 Timisoara, RO; Emergency Clinical Municipal Hospital Timisoara, RO.
13. Dept. of Surgery II- Division of Surgery I, “Victor Babes” University of Medicine and Pharmacy Timisoara, Romania; Eftimie Murgu Sq. no. 2, 300041 Timisoara, RO; County Emergency Hospital Timisoara, RO.
14. Dept. of Morphologic Microscopy - Division of Cellular and Molecular Biology; "Victor Babeș" University of Medicine and Pharmacy Timișoara, Romania; Eftimie Murgu Sq. no. 2, 300041 Timișoara, RO; County Emergency Hospital Timisoara, RO.
*Equal contributions. These authors drafted the article for intellectual content, and gave the final approval of the article to be published.
#Equal contributions to the laboratory assessments and article revision.

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Citation:
Petrica L, Hogea E, Gadalean F, Vlad A, Vlad M, Dumitrascu V, Velciov S, Gluhovschi C, Bob F, Ursoniu S, Jianu DC, Matusz P, Pusztai AM, Motoc A, Cretu OM, Radu D, Milas O, Golea-Secara A, Simulescu A, Mogos-Stefan M, Patruica M, Balint L, Ienciu S, Vlad D, Popescu R. Long noncoding RNAs may impact podocytes and proximal tubule function through modulating miRNAs expression in Early Diabetic Kidney Disease of Type 2 Diabetes Mellitus patients. Int J Med Sci 2021; 18(10):2093-2101. doi:10.7150/ijms.56551. Available from https://www.medsci.org/v18p2093.htm

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Abstract

Graphic abstract

Aims: Long noncoding RNAs (lncRNAs) play key roles in the pathophysiology of DKD involving actions of microRNAs (miRNAs). The aims of the study were to establish the involvement of selected lncRNAs in the epigenetic mechanisms of podocyte damage and tubular injury in DKD of type 2 diabetes mellitus (DM) patients in relation to a particular miRNAs profile.

Methods: A total of 136 patients with type 2 DM and 25 healthy subjects were assessed in a cross-sectional study concerning urinary albumin: creatinine ratio (UACR), eGFR, biomarkers of podocyte damage (synaptopodin, podocalyxin) and of proximal tubule (PT) dysfunction (Kidney injury molecule-1-KIM-1, N-acetyl-D-glucosaminidase-NAG), urinary lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), nuclear-enriched abundant transcript 1 (NEAT1), myocardial infarction-associated transcript (MIAT), taurine-upregulated gene 1 (TUG1), urinary miRNA21, 124, 93, 29a.

Results: Multivariable regression analysis showed that urinary lncMALAT1 correlated directly with urinary synaptopodin, podocalyxin, KIM-1, NAG, miRNA21, 124, UACR, and negatively with eGFR, miRNA93, 29a (p<0.0001; R2=0.727); urinary lncNEAT1 correlated directly with synaptopodin, KIM-1, NAG, miRNA21, 124, and negatively with eGFR, miRNA93, 29a (p<0.0001; R2=0.702); urinary lncMIAT correlated directly with miRNA93 and 29a, eGFR (p<0.0001; R2=0.671) and negatively with synaptopodin, KIM-1, NAG, UACR, miRNA21, 124 (p<0.0001; R2=0.654); urinary lncTUG1 correlated directly with eGFR, miRNA93, 29a, and negatively with synaptopodin, podocalyxin, NAG, miRNA21, 124 (p<0.0001; R2=0.748).

Conclusions: In patients with type 2 DM lncRNAs exert either deleterious or protective functions within glomeruli and PT. LncRNAs may contribute to DKD through modulating miRNAs expression and activities. This observation holds true independently of albuminuria and DKD stage.

Keywords: lncRNA, miRNA, podocyte, proximal tubule, diabetes mellitus