Published Online
on November 15, 2004

A more recent version of this article appeared on December 1, 2004

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Submitted on September 7, 2004
Revised on September 16, 2004

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

Jana Ortmann; Kerstin Amann; Ralf P. Brandes; Matthias Kretzler; Klaus Münter; Niranjan Parekh; Tobias Traupe; Melanie Lange; Thomas Lattmann; and Matthias Barton^*

From the Medizinische Poliklinik (J.O., T.T., M.L., T.L., M.B.), Universitätsspital Zürich, Switzerland; Pathologisches Institut (K.A.), Universität Erlangen-Nürnberg, Erlangen, Germany; Zentrum für Kardiovaskuläre Physiologie (R.P.B.), Klinikum der J.-W. Goethe Universität, Frankfurt, Germany; Medizinische Poliklinik (M.K.), Ludwig-Maximilians Universität München, Germany; Cardiovascular Research II (K.M.), Bayer AG, Wuppertal, Germany; and Institut für Physiologie und Pathophysiologie der Universität Heidelberg (N.P.), Germany.

^* To whom correspondence should be addressed. E-mail: barton{at}usz.ch.

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.

Key words: arterial presure • nephrosclerosis • DNA • kidney failure • renal artery • expression • kidney • renal disease

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