Glomerular Mesangial Cells: Electrophysiology and Regulation of Contraction

Abstract

Mesangial cells are smooth muscle-like pericytes that abut and surround the filtration capillaries within the glomerulus. Studies of the fine ultrastructure of the glomerulus show that the mesangial cell and the capillary basement membrane form a biomechanical unit capable of regulating filtration surface area as well as intraglomerular blood volume. Structural and functional studies suggest that mesangial cells regulate filtration rate in both a static and dynamic fashion. Mesangial excitability enables a homeostatic intraglomerular stretch reflex that integrates an increase in filtration pressure with a reduction in capillary surface area. In addition, mesangial tone is regulated by diverse vasoactive hormones. Agonists, such as angiotensin II, contract mesangial cells through a signal transduction pathway that releases intracellular stores of Ca2+, which subsequently activate nonselective cation channels and Cl- channels to depolarize the plasma membrane. The change in membrane potential activates voltage-gated Ca2+ channels, allowing Ca2+ cell entry and further activation of depolarizing conductances. Contraction and entry of cell Ca2+ are inhibited only when Ca2+-activated K+ channels (BK(Ca)) are activated and the membrane is hyperpolarized toward the K+ equilibrium potential. The mesangial BK(Ca) is a weak 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 BK(Ca) independent of sensitivity. This enables BK(Ca) to more effectively counter membrane depolarization and voltage-gated Ca2+ influx. After hyperpolarizing the membrane, BK(Ca) rapidly inactivates because of dephosphorylation by protein phosphatase 2A. Regulation of ion channels has been linked casually to hyperfiltration during early stages of diabetes mellitus. Determining the signaling pathways controlling the electrophysiology of glomerular mesangial cells is important for understanding how glomerular filtration rate is regulated in health and disease.

Canonical Transient Receptor Potential 1 Channel Is Involved in Contractile Function of Glomerular Mesangial Cells

“…MC contribute to the physiologic regulation of glomerular hemodynamics by responding to locally produced or circulating vasoactive peptides (1). Like smooth muscle cells, the contractility of MC is tightly controlled by [Ca 2ϩ ] i .…”

“…G lomerular mesangial cells (MC) are located within glomerular capillary loops and contribute to the physiologic regulation of glomerular hemodynamics (1). Altered responsiveness of MC to hormones is one of the major causes that lead to various renal diseases.…”

“…Altered responsiveness of MC to hormones is one of the major causes that lead to various renal diseases. Ca 2ϩ influx across the plasma membrane is a major component of MC responses to vasoconstrictors (1). Several types of Ca 2ϩ -conductive channels in the plasma membrane are involved in the physiologic processes.…”

“…Several types of Ca 2ϩ -conductive channels in the plasma membrane are involved in the physiologic processes. These channels include voltage-operated Ca 2ϩ channel (VOCC), receptor-operated channel (ROC), and recently found store-operated channel (SOC) (1,2). In contrast to the widely known VOCC, the molecular identity, physiologic significance, and regulatory mechanism of ROC and SOC in the glomerular contractile cells remain unknown.…”

Cloning and Functional Characterization of Novel Large Conductance Calcium-activated Potassium Channel β Subunits, hKCNMB3 and hKCNMB4

“…In neurons, BK channels are functionally colocalized with calcium channels (5,6), shape action potential wave forms (7,8), and modulate neurotransmitter release (9,10). In smooth muscle, BK channels regulate constriction in arteries (11), uterine contraction (12), and filtration rate in the kidney (13). Unlike other potassium channel families, BK channels can as yet only be attributed to a single gene, slowpoke (slo), that encodes the poreforming ␣ subunit of the channel.…”