Abstract-The cause of focal-segmental glomerulosclerosis as a consequence of physiological aging, which is believed to be inexorable, is unknown. This study investigated whether inhibition of endothelin-1, a growth-promoting peptide contributing to renal injury in hypertension and diabetes, affects established glomerulosclerosis and proteinuria in the aged kidney. We also determined the role of endothelin receptors for podocyte injury in vivo and in vitro. Aged Wistar rats, a model of spontaneous age-dependent glomerulosclerosis, were treated with the orally active endothelin subtype A (ET A ) receptor antagonist darusentan, and evaluation of renal histology, renal function studies, and expression analyses were performed. In vitro experiments using puromycin aminonucleoside to induce podocyte injury investigated the role of ET A receptor signaling for apoptosis, cytoskeletal injury, and DNA synthesis. In aged Wistar rats, established glomerulosclerosis and proteinuria were reduced by Ͼ50% after 4 weeks of darusentan treatment, whereas blood pressure, glomerular filtration rate, or tubulo-interstitial renal injury remained unaffected. Improvement of structural injury in glomeruli and podocytes was accompanied by a reduction of the expression of matrix metalloproteinase-9 and p21 Cip1/WAF1 . In vitro experiments blocking ET A receptors using specific antagonists or RNA interference prevented apoptosis and structural damage to podocytes induced by puromycin aminonucleoside. In conclusion, these results support the hypothesis that endogenous endothelin contributes to glomerulosclerosis and proteinuria in the aging kidney. The results further suggest that age-dependent glomerulosclerosis is not merely a "degenerative" but a reversible process locally confined to the glomerulus involving recovery of podocytes from previous injury. Key Words: arterial presure Ⅲ nephrosclerosis Ⅲ DNA Ⅲ kidney failure Ⅲ renal artery Ⅲ expression Ⅲ kidney Ⅲ renal disease A ging represents an important factor determining onset and course of disease and has become a significant issue in view of the anticipated increase of the aging population. Aging in humans and rodents progressively impairs renal function 1,2 and structure, the latter of which is characterized by damage of podocytes and mesangial matrix, as well as capillary hypertrophy and obliteration resulting in glomerulosclerosis. 2 The exact mechanisms underlying agedependent renal injury are unknown. In otherwise healthy individuals Ն65 years of age, even in the absence of known risk factors such as hypertension or diabetes, glomerulosclerosis is frequently present. 3 Currently, Ϸ1.4% of the US total population is affected, and the incidence is expected to increase to Ͼ2% within the next 15 years. 3 Glomerulosclerosis and proteinuria involve injury of podocytes, also known as glomerular epithelial cells that maintain an intact filtration barrier and control glomerular basement membrane turnover under normal conditions. 4 -7 In addition to cell-specific changes during aging, cell c...
