Endothelial Dysfunction of the Kidney in Sepsis

Glomerular and Peritubular Endothelium

Glomerular endothelial cells are unusually thin; around capillary loops, they have a cell thickness of approximately 50 to 150 nm, whereas in other locations, this thickness is approximately 500 nm. ECs in the glomerulus present large fenestrated areas constituting 20% to 50% of the entire endothelial surface. These fenestrations are typically 60 to 70 nm in diameter but, unlike renal peritubular ECs, do not seem to possess a thin (3–5 nm) diaphragm. In general, these fenestrations act as a sieving barrier to control the production of urine in the glomerulus, filtering plasma because of hydrostatic pressure. The kidney has one of the richest and most diverse EC populations found within any organ. The microcirculation of the kidney presents two specialized capillary beds connected in series: the glomerular capillary bed in the cortex for plasma filtration and the peritubular capillary bed, which forms the vasa recta responsible for electrolyte reabsorption in the outer and inner medulla. Thus the arrangement of ECs and the permeability of the endothelium differ for these two microcirculations. Glomerular microcirculation functions via continuous and fenestrated endothelium with no diaphragm, whereas it is more continuous and nonfenestrated in the descending vasa recta in peritubular microcirculation.

The endothelium must face and resist extreme physiologic conditions, such as large changes in oxygenation and osmolality. Indeed, ECs in the cortex are exposed to almost normal oxygen partial pressure and osmolality, whereas those in medullar microcirculation function in an osmolarity of up to 1200 mosmol/L ^-1 and a PO ₂ as low as 20 mm Hg. The microvascular arrangement has a specialized structure in the medulla. The vasa recta, connected in series with the juxtaglomerular microvasculature, surround the peritubular cells in the outer and inner medulla and are responsible for solute exchange. The ECs of these microvessels are exposed to countercurrent oxygen exchange, resulting in a gradient of decreasing oxygen tension (to approximately 10 mm Hg). Thus their functions differ considerably along the tubule. In addition, ECs are affected and injured by ischemia injury differently.

Interplay of Endothelium and Leukocytes

The inner lumen of ECs is exposed to blood flow, consisting of red blood cells, leukocytes, and plasma. In the physiologic state, endothelium–leukocyte interactions are limited. Five steps generally describe the interactions between ECs and leukocytes during inflammation, beginning with limited contact, then more prolonged contact, leukocyte rolling, strong adhesion, and finally transendothelial migration, a process referred to as diapedesis. ECs regulate leukocyte trafficking between circulating blood and the surrounding tissue. When activated, the endothelium exhibits enhanced endothelium–leukocyte interactions that are secondary to increased expressions of cell adhesion molecules (CAMs), such as intercellular adhesion molecule selectins (E-selectin and L-selectin), ICAM-1, ICAM-2, vascular adhesion molecule (VCAM), and platelet endothelial cell adhesion molecule (PECAM). The upregulation of CAMs promotes increased adhesion, rolling, and transmigration of circulating leukocytes. Many integrins also are involved in the adhesion of polymorphonuclear leukocytes and monocytes in the proximal tubule and serve as transcellular mechanotransducers.