We have recently identified a novel human gene, megsin, which is a new serine protease inhibitor (serpin) predominantly expressed in the kidney. Our previous studies suggested a role of megsin in the pathogenesis of human renal diseases, but its exact biopathological significance remained unknown. During the analysis of experimental animals overexpressing the human megsin gene, we unexpectedly generated a "serpinopathy" model involving the kidney and pancreas and discovered a novel mechanism of renal injury, that is, cellular damage by endoplasmic reticulum (ER) stress caused by conformational disorder of protein tertiary structure within the ER. In vitro induction of ER stress may play a role in renal cell injury by various stimuli, but the involvement of ER stress in human renal disease remains elusive. Further research for ER structure and function may open new exciting prospects in the pathology of human renal diseases.