Downregulation of fibrosis related hsa-miR-29c-3p in human CAKUT

Abstract

Congenital anomalies of the kidney and urinary tract (CAKUT) represent structural and functional urinary system malformations and take place as one of the most common congenital malformations with an incidence of 1:500. Ureteral obstruction-induced hydronephrosis is associated with renal fibrosis and chronic kidney diseases in the pediatric CAKUT. We aimed to construct interaction network of previously bioinformatically associated miRNAs with CAKUT differentially expressed genes in order to prioritize those associated with fibrotic process and to experimentally validate the expression of selected miRNAs in CAKUT patients compared to control group. We constructed interaction network of hsa-miR-101-3p, hsa-miR-101-5p and hsa-miR-29c-3p that showed significant association with fibrosis. The top enriched molecular pathway was extracellular matrix-receptor interaction (adjusted p = .0000263). We experimentally confirmed expression of three miRNAs (hsa-miR-29c-3p, hsa-miR-101-3p and hsa-miR-101-5p) in obstructed ureters (ureteropelvic junction obstruction and primary obstructive megaureter) and vesicoureteral reflux. The hsa-miR-29c-3p was shown to have lower expression in both patient groups compared to controls. Relative levels of hsa-miR-101-5p and hsa-miR-101-3p showed significant positive correlations in both groups of patients. Statistically significant correlation was observed between hsa-miR-101 (-3p and -5p) and hsa-miR-29c-3p only in the obstructed group. The significant downregulation of anti-fibrotic hsa-miR-29c-3p in obstructive CAKUT could explain activation of genes involved in fibrotic processes. As miRNAs are promising candidates in therapeutic approaches our results need further measurement of fibrotic markers or assessment of extent of fibrosis and functional evaluation of hsa-miR-29c.

Keywords:

• Bioinformatics
• CAKUT
• fibrosis
• miR-29c
• miR-101

Authors’ contributions

A.S., M.Z., I.J. and M.K. conceptualized and designed the study; N.M., K.M. and M.C. conducted the experiments and statistical analysis; I.J. interpreted the data; N.M., I.J., K.M. and A.S. wrote the manuscript; A.S., I.J. and M.Z. revised the manuscript; A.S. edited the manuscript; M.C. and M.K. collected samples. All authors have read and approved the final manuscript.

Disclosure statement

The authors declare that they have no conflict of interest.

Informed consent

Informed consent was obtained from all participants or their parents

Additional information

Funding

This work was supported by the Ministry of Education, Science and Technological Development, Republic of Serbia (Registration number: 451-03-68/2022-14/200017).