Role of Podocytes for Reversal of Glomerulosclerosis and Proteinuria in the Aging Kidney After Endothelin Inhibition

TLDR

The etiology of age‑related focal‑segmental glomerulosclerosis is unknown. The study examined whether endothelin‑1 inhibition reverses established glomerulosclerosis and proteinuria in aged kidneys and assessed the role of endothelin receptors in podocyte injury. Aged Wistar rats received the oral ET‑A antagonist darusentan, and renal histology, function, and expression were evaluated, while in vitro puromycin‑induced podocyte injury examined ET‑A signaling effects on apoptosis, cytoskeletal integrity, and DNA synthesis. Darusentan treatment reduced glomerulosclerosis and proteinuria by over 50% without affecting blood pressure, GFR, or tubulo‑interstitial injury, lowered MMP‑9 and p21 expression, and in vitro ET‑A blockade prevented podocyte apoptosis and damage, supporting endothelin’s role and the reversibility of age‑dependent glomerulosclerosis.

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 >50% 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.