Cytochrome c mediates apoptosis in hypertensive nephrosclerosis in Dahl/Rapp rats.
BACKGROUND
Renal damage from hypertension is the second most common cause of end-stage renal failure in the United States. The pathogenesis of this process is incompletely understood. The Dahl/Rapp salt-sensitive (S) rat is a model of low-renin hypertension, but these rats also develop renal lesions 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 normal, but by day 21 on the high-salt diet, S rats displayed morphological evidence of severe renal injury that included glomerulosclerosis, arteriolosclerosis, and tubulointerstitial damage. Apoptosis was demonstrated in kidneys of hypertensive S rats by day 7. Cytoplasmic content of cytochrome c was increased in the kidney cortex of hypertensive S rats, and isolated mitochondria showed inappropriate release of cytochrome c sufficient to activate caspase-3 in vitro. Activation of caspase-9 and caspase-3 was observed only in kidney cortex 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 caspase-3. The findings support a primary role of cytochrome c release and apoptosis in the pathogenesis of hypertensive nephrosclerosis in S rats.
Ying
W Z
WZ
Nephrology Research and Training Center, Comprehensive Cancer Center, University of Alabama at Birmingham 35294, USA.
Sanders
P W
PW
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism / Q000502:physiology*; D004039:Diet, Sodium-Restricted; D004789:Enzyme Activation; D006973:Hypertension / Q000150:complications* / Q000473:pathology; D007668:Kidney / Q000378:metabolism; D007672:Kidney Cortex / Q000201:enzymology; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D009400:Nephrosclerosis / Q000209:etiology* / Q000503:physiopathology*; D051381:Rats; D020303:Rats, Inbred Dahl; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D003574:Cytochrome c Group; C505407:CASP3 protein, human; C506433:CASP9 protein, human; C505410:Casp3 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases