Renal Cellular Responses to Toxicant Exposures

Nephrotoxic insult to the nephron

Uninjured cells

Compensatory hypertrophy

Cellular adaptation

Injured cells juj^) Cell death

Cellular proliferation

Cellular repair

Re-epithelialization

Differentiation iz lz

Cellular adaptation

Structural and functional recovery of the nephron

Intact tubular epithelium

Intact tubular epithelium

Loss of polarity, tightjunction integrity, cell-substrate adhesion, simplification of brush border

Cytoskeleton | Extracellular matrix 0 Na+/K+=ATPase •c p Integrin o RGD peptide

Cell death

Cast formation and tubuler obstruction

Cell death

Necrosis

Necrosis

Sloughing of viable and nonviable cells with intraluminal cell-cell adhesion

Sloughing of viable and nonviable cells with intraluminal cell-cell adhesion

Cast formation and tubuler obstruction

Apoptosis

Apoptosis

FIGURE 15-9

After injury, alterations can occur in the cytoskeleton and in the normal distribution of membrane proteins such as Na+, K+-ATPase and p integrins in sublethally injured renal tubular cells. These changes result in loss of cell polarity, tight junction integrity, and cell-substrate adhesion. Lethally injured cells undergo oncosis or apoptosis, and both dead and viable cells may be sloughed into the tubular lumen. Adhesion of sloughed cells to other sloughed cells and to cells remaining adherent to the basement membrane may result in cast formation, tubular obstruction, and further compromise the glomerular filtration rate. (Adapted from Fish and Molitoris [1], and Gailit et al. [2]; with permission.)

FIGURE 15-10

Potential sites where nephrotoxicants can interfere with the struc tural and functional recovery of nephrons.

Sublethally Migrating Cell injured cells spreading cells proliferation

Sublethally Migrating Cell injured cells spreading cells proliferation

of cell repair of cell migration/spreading of cell proliferation
Time after exposure, d

FIGURE 15-11

Inhibition and repair of renal proximal tubule cellular functions after exposure to the model oxidant t-butylhydroperoxide. Approximately 25% cell loss and marked inhibition of mitochon-drial function active (Na+) transport and Na+-coupled glucose transport occurred 24 hours after oxidant exposure. The activity of the brush border membrane enzyme ^-glutamyl transferase (GGT) was not affected by oxidant exposure. Cell proliferation and migration or spreading was complete by day 4, whereas active Na+ transport and Na+-coupled glucose transport did not return to control levels until day 6. These data suggest that selective physiologic functions are diminished after oxidant injury and that a hierarchy exists in the repair process: migration or spreading followed by cell proliferation forms a monolayer and antedates the repair of physiologic functions. (Data from Nowak et al. [3].)

Blebbing

Budding

Phagocytosis inflammation

Phagocytosis by macrophages or nearby cells

Blebbing

Budding

Phagocytosis inflammation

FIGURE 15-12

Phagocytosis by macrophages or nearby cells

Apoptosis and oncosis are the two generally recognized forms of cell death. Apoptosis, also known as programmed cell death and cell suicide, is characterized morphologically by cell shrinkage, cell budding forming apoptotic bodies, and phagocytosis by macrophages and nearby cells. In contrast, oncosis, also known as necrosis, necrotic cell death, and cell murder, is characterized morphologically by cell and organelle swelling, plasma membrane bleb-bing, cell lysis, and inflammation. It has been suggested that cell death characterized by cell swelling and lysis not be called necrosis or necrotic cell death because these terms describe events that occur well after the cell has died and include cell and tissue breakdown and cell debris. (From Majno and Joris [4]; with permission.)

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