Background. Renal damage from hypertension is the second most common cause
of end-stage renal failure in the United States. The pathogenesis of this p
rocess is incompletely understood. The Dahl/Rapp salt-sensitive (S) rat is
a model of low-renin hypertension, but these rats also develop renal lesion
s that are virtually identical to human hypertensive nephrosclerosis.
Methods. To explore apoptosis as a mechanism of progressive renal injury in
S rats, age- and sex-matched S and Sprague-Dawley (SD) rats were placed on
either 0.3 or 8.0% NaCl diets, which were continued for 21 days.
Results. At day 7, renal histology appeared relatively nor mal, but by day
21 on the high-salt diet, S rats displayed morphological evidence of severe
renal injury that included glomerulosclerosis. arteriolosclerosis, and tub
ulointerstitial damage. Apoptosis was demonstrated in kidneys of hypertensi
ve S rats by day 7. Cytoplasmic content of cytochrome c was increased in th
e kidney cortex of hypertensive S rats, and isolated mitochondria showed in
appropriate release of cytochrome c sufficient to activate caspase-3 in vit
ro. Activation of caspase-9 and caspase-3 was observed only in kidney corte
x from hypertensive S rats.
Conclusions. Kidneys from hypertensive S rats display apoptosis related to
mitochondrial release of cytochrome c and activation of caspase-9 and caspa
se-3. The findings support a primary role of cytochrome c release and apopt
osis in the pathogenesis of hypertensive nephrosclerosis in S rats.