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

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2004-12, Vol.44 (6), p.974-981
• Main Authors: Ortmann, Jana, Amann, Kerstin, Brandes, Ralf P, Kretzler, Matthias, Münter, Klaus, Parekh, Niranjan, Traupe, Tobias, Lange, Melanie, Lattmann, Thomas, Barton, Matthias
• Format: Article
• Language: English
• Subjects: Aging - physiology; Animals; Antihypertensive agents; Apoptosis; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure; Cardiology. Vascular system; Cardiovascular system; Cell Cycle Proteins - genetics; Cyclin-Dependent Kinase Inhibitor p21; Disease Models, Animal; DNA - biosynthesis; Endothelin A Receptor Antagonists; Endothelin-1 - antagonists & inhibitors; Endothelin-1 - physiology; Experimental diseases; Gene Expression; Gene Silencing; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental - drug therapy; Glomerulosclerosis, Focal Segmental - pathology; Glomerulosclerosis, Focal Segmental - physiopathology; Kidney - cytology; Kidney - drug effects; Kidney - physiology; Kidney Glomerulus - metabolism; Kidney Glomerulus - pathology; Male; Matrix Metalloproteinase 9 - genetics; Medical sciences; Pharmacology. Drug treatments; Phenylpropionates - pharmacology; Proteinuria - drug therapy; Proteinuria - etiology; Pyrimidines - pharmacology; Rats; Rats, Wistar; Receptor, Endothelin A - physiology; Signal Transduction
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/01.HYP.0000149249.09147.b4

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 (ETA) 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 ETA 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. In vitro experiments blocking ETA 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.