The Ischemic Epithelial Cell

fx Functional renal tubules

Ischemic insult fx Functional renal tubules

Ischemic insult

, Uninjured cells r

Injured cells

, Uninjured cells r

Injured cells lATP; Î[CA2+1; ÎFree radicals; Other changes?

Tight junction disruption

Apical-basolateral polarity disruption

Microfilament disruption

Dysfunctional renal tubular epithelial cells

Remove insult

Continued insult

Cellular repair

Cell loss (detachment or death)

Cell regenertation, differentiation, and morphogenesis

Remove insult

FIGURE 16-1

Ischemic acute renal failure (ARF). Flow chart illustrates the cellular basis of ischemic ARF. As described above, renal tubule epithelial cells undergo a variety of biochemical and structural changes in response to ischemic insult. If the duration of the insult is sufficiently short, these alterations are readily reversible, but if the insult continues it ultimately leads to cell detachment and/or cell death. Interestingly, unlike other organs in which ischemic injury often leads to permanent cell loss, a kidney severely damaged by ischemia can regenerate and replace lost epithelial cells to restore renal tubular function virtually completely, although it remains unclear how this happens.

FIGURE 16-3

FIGURE 16-2

Typical renal epithelial cell. Diagram of a typical renal epithelial cell. Sublethal injury to polarized epithelial cells leads to multiple lesions, including loss of the permeability barrier and apical-basolat-eral polarity [7-12]. To recover, cells must reestablish intercellular junctions and repolarize to form distinct apical and basolateral domains characteristic of functional renal epithelial cells. These junctions include those necessary for maintaining the permeability barrier (ie, tight junctions), maintaining cell-cell contact (ie, adherens junctions and desmosomes), and those involved in cell-cell communication (ie, gap junctions). In addition, the cell must establish and maintain contact with the basement membrane through its integrin receptors. Thus, to understand how kidney cells recover from sublethal ischemic injury it is necessary to understand how renal epithelial cells form these junctions. Furthermore, after lethal injury to tubule cells new cells may have to replace those lost during the ischemic insult, and these new cells must differentiate into epithelial cells to restore proper function to the tubules.

FIGURE 16-3

The tight junction. The tight junction, the most apical component of the junctional complex of epithelial cells, serves two main functions in epithelial cells: 1) It separates the apical and basolateral plasma membrane domains of the cells, allowing for vectorial transport of ions and molecules; 2) it provides the major framework for the paracellular permeability barrier, allowing for generation of chemical and electrical gradients [31]. These functions are critically important to the proper functioning of renal tubules. The tight junction is comprised of a number of proteins (cytoplasmic and transmembrane) that interact with a similar group of proteins between adjacent cells to form the permeability barrier [16, 32-37]. These proteins include the transmembrane protein occludin [35, 38] and the cytosolic proteins zonula occludens 1 (ZO-1), ZO-2 [36], p130, [39], cingulin [33, 40], 7H6 antigen [34] and symplekin [41], although other as yet unidentified components likely exist. The tight junction also appears to interact with the actin-based cytoskeleton, probably in part through ZO-1-fodrin interactions.

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