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 ... Show moreThis 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. Show less
AIMS MicroRNA-126 (miR-126), which is enriched in endothelial cells, plays a role in angiogenesis. Based on the seed sequence, miR-126 can also be predicted to regulate vasculogenesis by modulating... Show moreAIMS MicroRNA-126 (miR-126), which is enriched in endothelial cells, plays a role in angiogenesis. Based on the seed sequence, miR-126 can also be predicted to regulate vasculogenesis by modulating the endothelial expression of stromal cell-derived factor-1 (SDF-1). METHODS AND RESULTS Using miR-reporter constructs, we first validated that miR-126 inhibits SDF-1 expression in endothelial cells in vitro. Next, we investigated the potential relevance of this observation with respect to the mobilization of progenitor cells. For this, we studied the migration of human CD34+ progenitor cells towards chemotactic factors present in endothelial cell-conditioned medium. Antagomir-induced silencing of miR-126 elevated SDF-1 expression by human umbilical vein endothelial cells and enhanced migration of the CD34+ cells. In a murine model of hind limb ischaemia, a striking increase in the number of circulating Sca-1(+)/Lin(-) progenitor cells in antagomir-126-treated mice was observed when compared with scramblemir-treated controls. Immunohistochemical staining of capillaries in the post-ischaemic gastrocnemius muscle of miR-126-silenced mice revealed elevated SDF-1 expressing CD31-positive capillaries, whereas a mobilizing effect of miR-126 inhibition was not detected in healthy control animals. CONCLUSION miR-126 can regulate the expression of SDF-1 in endothelial cells. In the context of an ischaemic event, systemic silencing of miR-126 leads to the mobilization of Sca-1(+)/Lin(-) progenitor cells into the peripheral circulation, potentially in response to elevated SDF-1 expression by endothelial cells present in the ischaemic tissue. Show less
Solingen, C. van; Monge, M.; Vries, D.K. de; Seghers, L.; Vries, M.R. de; Bijkerk, R.; ... ; Zonneveld, A.J. van 2010
