Chronic renal injury and high blood pressure are mechanistically related, complex diseases with enormous socio-economic impact. We developed a proteomic approach to find microRNA-target pairs that might be functionally relevant to the regulation of renal physiology in rats in vivo. The approach was further applied to analyze human renal epithelial cells and identify microRNA-target pairs potentially involved in maintaining epithelial characteristics. miR-382 was found to target superoxide dismutase 2 and contribute to loss of epithelial characteristics and the development of renal interstitial fibrosis. In a widely used genetic rat model of hypertension and renal injury, miR-29b was found to target a large group of extracellular matrix genes and protect the kidney from fibrotic injury. These studies, together with several recent studies from other investigators, are beginning to reveal a significant role of microRNA in the complex molecular network underlying the development of hypertension and renal injury.