GLOMERULAR MESANGIAL CELLS - ELECTROPHYSIOLOGY AND REGULATION OF CONTRACTION

Mesangial cells are smooth muscle-like pericytes that abut and surroun d the filtration capillaries within the glomerulus. Studies of the fin e ultrastructure of the glomerulus show that the mesangial cell and th e capillary basement membrane form a biomechanical unit capable of reg ulating filtration surface area as well as intraglomerular blood volum e. Structural and functional studies suggest that mesangial cells regu late filtration rate in both a static and dynamic fashion. Mesangial e xcitability enables a homeostatic intraglomerular stretch reflex that integrates an increase in filtration pressure with a reduction in capi llary surface area. In addition, mesangial tone is regulated by divers e vasoactive hormones. Agonists, such as angiotensin IT, contract mesa ngial cells through a signal transduction pathway that releases intrac ellular stores of Ca2+, which subsequently activate nonselective catio n channels and Cl- channels to depolarize the plasma membrane. The cha nge in membrane potential activates voltage-gated Ca2+ channels, allow ing Ca2+ cell entry and further activation of depolarizing conductance s. Contraction and entry of cell Ca2+ are inhibited only when Ca2+-act ivated K+ channels (BKCa) are activated and the membrane is hyperpolar ized toward the K+ equilibrium potential. The mesangial BKCa, is a wea k regulator of contraction in unstimulated cells; however, the gain of the feedback is increased by atrial natriuretic peptide, nitric oxide , and the second messenger cGMP, which activates protein kinase G and decreases both the voltage and Ca2+ activation thresholds of BKCa inde pendent of sensitivity. This enables BKCa to more effectively counter membrane depolarization and voltage-gated Ca2+ influx. After hyperpola rizing the membrane, BKCa rapidly inactivates because of dephosphoryla tion by protein phosphatase 2A. Regulation of ion channels has been li nked casually to hyperfiltration during early stages of diabetes melli tus. Determining the signaling pathways controlling the electrophysiol ogy of glomerular mesangial cells is important for understanding how g lomerular filtration rate is regulated in health and disease.