title: Role of podocytes for reversal of glomerulosclerosis and proteinuria in the aging kidney after endothelin inhibition.
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 p21Cip1/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.
authors.affiliation: Medizinische Poliklinik, Universitätsspital Zürich, Switzerland.
authors.forename: Jana
authors.initials: J
authors.lastname: Ortmann
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Brandes
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.forename: Klaus
authors.initials: K
authors.lastname: Münter
authors.forename: Niranjan
authors.initials: N
authors.lastname: Parekh
authors.forename: Tobias
authors.initials: T
authors.lastname: Traupe
authors.forename: Melanie
authors.initials: M
authors.lastname: Lange
authors.forename: Thomas
authors.initials: T
authors.lastname: Lattmann
authors.forename: Matthias
authors.initials: M
authors.lastname: Barton
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D001794:Blood Pressure; D018797:Cell Cycle Proteins / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004247:DNA / Q000096:biosynthesis; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D015870:Gene Expression; D020868:Gene Silencing; D005919:Glomerular Filtration Rate; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D010666:Phenylpropionates / Q000494:pharmacology; D011507:Proteinuria / Q000188:drug therapy / Q000209:etiology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000502:physiology; D015398:Signal Transduction
chemical_list: C493958:Cdkn1a protein, rat; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; C107831:darusentan; D004247:DNA; D020780:Matrix Metalloproteinase 9