Investigating the potential role of the formin protein mDia1 in extracellular matrix assembly and diabetic kidney disease

Abstract

Diabetic kidney disease is a serious yet common complication of diabetes that has grown in prevalence in recent years. The disease is characterized by impairment of the glomerulus, the filtering unit of the kidney, due to excessive accumulation of extracellular matrix (ECM). The mechanism for matrix accumulation is not entirely known, but recent research has provided evidence for the importance of RAGE: the receptor for advanced glycation endproduct (AGE) modifications, which occur as a result of high glucose conditions. Here, we focus on the downstream signal mediator of RAGE, mDia1. The formin protein mDia1 not only mediates RAGE signaling but is also a principal effector of RhoA GTPase, which is required for matrix assembly. These roles of mDia1 point to its potential involvement in matrix assembly and in the matrix accumulation that occurs in diabetic kidney disease. In this paper, we investigate whether mDia1 is important for matrix assembly. The small molecular inhibitor SMIFH2 was used to inhibit all formin proteins in the cell. We confirm the importance of formins for the cytoskeleton and highlight the limitations of the inhibitor. Next we performed RNA interference to knockdown expression of mDia1 and analyzed the effects on matrix production. Our results do not show a difference in matrix upon knockdown of mDia1. We conclude that mDia1 is not essential for matrix assembly and propose alternate explanations for its role in the cell and the diabetic kidney.