Renin-angiotensin system in ureteric bud branching morphogenesis: insights into the mechanisms

Branching morphogenesis of the ureteric bud (UB) is a key developmental process that controls organogenesis of the entire metanephros. Notably, aberrant UB branching may result in a spectrum of congenital anomalies of the kidney and urinary tract (CAKUT). Genetic, biochemical and physiological studies have demonstrated that the renin-angiotensin system (RAS), a key regulator of the blood pressure and fluid/electrolyte homeostasis, also plays a critical role in kidney development. All the components of the RAS are expressed in the metanephros. Moreover, mutations in the genes encoding components of the RAS in mice or humans cause diverse types of CAKUT which include renal papillary hypoplasia, hydronephrosis, duplicated collecting system, renal tubular dysgenesis, renal vascular abnormalities, abnormal glomerulogenesis and urinary concentrating defect. Despite widely accepted role of the RAS in metanephric kidney and renal collecting system (ureter, pelvis, calyces and collecting ducts) development, the mechanisms by which an intact RAS exerts its morphogenetic actions are incompletely defined. Emerging evidence indicates that defects in UB branching morphogenesis may be causally linked to the pathogenesis of renal collecting system anomalies observed under conditions of aberrant RAS signaling. This review describes the role of the RAS in UB branching morphogenesis and highlights emerging insights into the cellular and molecular mechanisms whereby RAS regulates this critical morphogenetic process.