243

or lethal factors or compete for such

factors.

Angiotensin II,

Intracellular

4.1. Survival factors

ROS, TGFβ1

milieu: high

Survival factors for tubular and mesan-

gial cells and podocytes include insulin-

like growth factor 1 (IGF-1), hepatocyte

Podocyte

growth factor (HGF), vascular endothe-

GBM

lial growth factor (VEGF), GDNF, ery-

thropoietin, and parathyroid hormone–

related protein. These factors activate

the PI3K/AKT survival pathway. AKT

has several antiapoptotic actions. AKT

phosphorylates and inhibits proapop-

totic factors such as BAD. Unphospho-

rylated BAD binds to BclxL, blocking its

survival function. BAD dephosphoryla-

tion is observed in tubular cells exposed

to proapoptotic stimuli.

Cultured tubular cells exposed to

degradation products; ROS, reactive oxygen species.

survival factors develop a general intra-

nephrons), and death receptors induce

apoptosis of

cellular milieu favoring survival that

includes low levels of proapoptotic Fas receptor and

Bax and higher levels of antiapoptotic BclxL and Bcl2.

Renal ischemia is the primary pathogenic mechanism

In addition, compensatory survival pathways are acti-

in renal vascular injury. Ischemia as a contributor to

vated in the course of injury that may limit the extent of

renal cell apoptosis has been usually studied in cell mod-

injury and accelerate recovery. AKT is activated in tubu-

els or animal models of AKI.

lar cells after renal ischemia/reperfusion injury, tubu-

Human PKD is a group of hereditary diseases caused

lar cell BclxL

is increased in experimental AKI, and

by mutations in genes that encode primary cilia proteins.

VEGF is increased in cyclosporin A (CsA) nephrotox-

The most frequently mutated gene is pkd1. PKD is char-

icity in vivo and in cultured tubular cells. Podocyte

acterized by increased tubular proliferation, apoptosis,

Hsp27 is increased in rat models of podocyte injury.

and dedifferentiation, leading to the growth of fluid-

Over-expression of Hsp27 in cultured podocytes pre-

filled cysts in kidneys. No effective treatment is currently

served morphological features and improved podocyte

available. Bcl-2–/– mice develop polycystic kidneys, but

survival. The GDNF receptor tyrosine kinase, RET, was

the mechanisms differ from those of pkd1–/– mice in that

upregulated in podocytes in experimental proteinuric

disease in the latter is not prevented by absence of Bim.

nephropathies and in cultured mouse podocytes after

At present, the relationship between uncontrolled prolif-

injury induced by sublytic C5b-9. GDNF and VEGF are

eration and apoptosis has not been clarified. Both cas-

also induced during podocyte injury and behave as

pase inhibitors and the cell cycle inhibitor roscovitine

autocrine survival factors. Clusterin (SPG40) is a multi-

decrease proliferation and apoptosis and prevent dis-

functional protein whose expression is increased in renal

ease progression in animal models.

injury and protects cells from apoptosis in vitro and in

vivo. Exogenous clusterin prevents peroxide hydrogen

4. REGULATION OF APOPTOSIS IN KIDNEY CELLS

cytotoxicity in tubular cells. Interference with these com-

pensatory mechanisms aggravates renal injury as exem-

Renal cell death is usually a response to the cell

plified by the more severe renal injury when endogenous

microenvironment. The absence of certain factors (sur-

VEGF is neutralized in CsA nephrotoxicity. Therapeutic

vival factors) or the presence of lethal factors pro-

interventions designed to potentiate endogenous adap-

motes apoptosis. Surrounding cells, soluble media-

tive pathways have been successfully employed in exper-

tors, and the extracellular matrix regulate cell death

imental AKI and CKD. IGF-1, HGF, erythropoietin, and

and survival. Surrounding cells can synthesize survival

non-erythropoietic erythropoietin-like molecules have