Rho Kinase Inhibition: A New Approach for Treating Diabetic Nephropathy?

Abstract

Rho family GTPases have received increasing attention as critical regulators of cell function (1). Initially, they were shown to regulate actin dynamics, thereby modulating development, cell migration, immune responses, and cancer cell invasion and metastasis. More recent studies have shown that they are also involved in cell-cell adhesion and cell cycle progression. RhoA is one of the most widely studied of the 22 mammalian members of the family, and the serine-threonine kinase Rho kinase (ROCK) is a major RhoA effector. RhoA/ROCK has a number of functions in the kidney. RhoA/ROCK enhances Ca2+-dependent vascular smooth muscle contraction, thereby modulating tone (2–4). The potent vasoconstrictor angiotensin II (AngII) activates ROCK in smooth muscle cells. The ROCK inhibitors fasudil and Y-27632 dilate afferent and efferent arterioles and reverse AngII-dependent arteriolar vasoconstriction. At the cellular level, RhoA/ROCK mediates cytoskeletal rearrangement in renal tubule cells, mesangial cells and podocytes and may contribute to epithelial-mesenchymal transdifferentiation, which may be important in the development of renal fibrosis. ROCK inhibitors have renoprotective effects in a number of models of kidney damage (2). They prevent tubulointerstitial fibrosis following unilateral ureteral obstruction, and decrease structural and functional damage in hypertensive models without affecting blood pressure. When activated, RhoA translocates from the cytoplasm to the cell membrane. RhoA translocation to …