MicroRNAs in kidney health and disease

Abstract

This thesis describes a role for microRNAs in kidney (patho)physiology. First, it is shown that miR-155 negatively regulates RhoA signaling in TGF-induced endothelial-to-mesenchymal-transition (EndoMT). EndoMT associates with reorganization of the cytoskeleton and production of extracellular matrix, and is potentially involved in the loss of microvascular capillaries in renal fibrosis. Second, we focused on ischemia/reperfusion-injury (IRI), a central event in conditions such as acute kidney injury and organ transplantation, where the renal peritubular capillary network is considered the primary site of injury. Consequently, capillary integrity is a key determinant for preservation of renal function. Systemic silencing of miR-126 impairs ischemia-induced angiogenesis, and affects mobilization of vasculogenic progenitor cells, potentially by modulating SDF-1 expression. Furthermore, overexpression of miR-126 in the hematopoietic compartment protects against renal IRI by promoting vascular integrity. We identified miR-132 to be involved in renal fibrosis. Lineage analysis of kidney stroma showed that pericytes are the major source of myofibroblasts Silencing miR-132 results in decreased pericyte differentiation towards myofibroblasts. Subsequently we demonstrated that miR-132 regulates diuresis by altering Aquaporin-2 localization in collecting ducts, which is responsible for water-reabsorption, by modulating vasopressin- and prostaglandin-dependent pathways. This thesis illustrates the essential role that microRNAs play in kidney health and disease.