miR-127-3p as a novel mediator in fibrosis development and macrophage polarization in Chronic Kidney Disease

Resumen

Chronic Kidney Disease (CKD) is worldwide recognized as a priority health problem because of its high prevalence and incidence. It courses with a long clinically silent period, therefore diagnosis and treatment occur during advanced stages of the disease. Identification of molecular mechanisms underlying chronic renal injury and searching for early biomarkers of CKD are essential for improving our understanding of CKD pathophysiology and patient management. microRNAs (miRNAs) are key regulators of gene expression that have emerged as a novel therapeutic target and useful biomarkers for pathology. In our lab we identified a set of miRNAs, including miR-127-3p, that remain altered after an AKI episode. We also demonstrated the protector role of miR-127-3p against ischemic injury in renal tubular cells. Moreover, bibliography has described miR-127-3p as a mediator in macrophage polarization during lung fibrosis. For all above, we aim to investigate the role of miR-127-3p in macrophage polarization during renal fibrosis underlying CKD and its modulation as a novel therapeutic strategy for the disease. For this, we have studied miR-127-3p expression in a mouse model of renal fibrosis (UUO), and the effect of its exogenous modulation during disease development. We have demonstrated miR-127-3p increases along disease progression in proximal tubules, correlating with fibrosis and the inflammatory response in which macrophages are key cells involved. Besides, we have demonstrated that inhibition of miR-127-3p expression in UUO mice aggravates disease progression and exacerbates associated inflammatory response, including macrophages. Moreover, we have studied the expression of miR-127-3p and the effect of its modulation in naïve murine macrophages (Mφ) and different induced phenotypes (M1[LPS] and M2[IL-4]). Results have shown that the expression of miR-127-3p does not change depending on the stimulus received. However, NOS2 expression, as a M1 macrophage marker, shows a positive tendency when the miRNA is inhibited in the cells. On the other hand, miRNA over-expression in the M2a [IL-4] phenotype leads to a decrease of NOS2, which suggests that the induction of miR-127-3p expression along the kidney injury modulate macrophages response and contribute to disease outcome. Based on these findings, we have tried different viral-based particles and administration approaches, and finally, we have successfully induced miR-127-3p expression in the renal cortex of mice using lentiviral particles injected through the renal arteria. Finally, decreased serum levels of miR-146a-3p, miR-27a-3p, and miR-93-3p have been associated with CKD progression. Whereas miR-127-3p, miR-146a-3p, miR-27a-3p, and miR-26b-5p serum levels have demonstrated correlation with renal damage parameters. In summary, all these results have revealed that miR-127-3p is involved in renal fibrosis as an important mediator of CKD development by affecting macrophages polarization, and therefore its modulation could be a potential therapeutic approach for CKD. Moreover, some studied miRNAs could serve as useful and minimum-invasive biomarkers that contribute to CKD stratification and patient management.