Johannes Leierer1, Michael Rudnicki1, Susie-Jane Braniff1, Paul Perco2, Christian Koppelstaetter1, Irmgard Mühlberger2, Susanne Eder1, Julia Kerschbaum1, Christoph Schwarzer3, Andrea Schroll4, Günter Weiss4, Stefan Schneeberger5, Silvia Wagner6, Alfred Königsrainer6, Georg A Böhmig7, Gert Mayer1. 1. Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria. 2. Emergentec Biodevelopment GmbH, Vienna, Austria. 3. Department of Pharmacology, Medical University Innsbruck, Innsbruck, Austria. 4. Department of Internal Medicine VI, Clinical Immunology and Infectious Diseases, Medical University, Innsbruck, Austria. 5. Center of Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Medical University Innsbruck, Innsbruck, Austria. 6. Department of General, Visceral and Transplant Surgery, University of Tübingen, Tübingen, Germany. 7. Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria.
Abstract
BACKGROUND: Human lifespan is increasing continuously and about one-third of the population >70 years of age suffers from chronic kidney disease. The pathophysiology of the loss of renal function with ageing is unclear. METHODS: We determined age-associated gene expression changes in zero-hour biopsies of deceased donor kidneys without laboratory signs of impaired renal function, defined as a last serum creatinine >0.96 mg/dL in females and >1.18 mg/dL in males, using microarray technology and the Significance Analysis of Microarrays routine. Expression changes of selected genes were confirmed by quantitative polymerase chain reaction and in situ hybridization and immunohistochemistry for localization of respective mRNA and protein. Functional aspects were examined in vitro. RESULTS: Donors were classified into three age groups (<40, 40-59 and >59 years; Groups 1, 2 and 3, respectively). In Group 3 especially, genes encoding for metallothionein (MT) isoforms were more significantly expressed when compared with Group 1; localization studies revealed predominant staining in renal proximal tubular cells. RPTEC/TERT1 cells overexpressing MT2A were less susceptible towards cadmium chloride-induced cytotoxicity and hypoxia-induced apoptosis, both models for increased generation of reactive oxygen species. CONCLUSIONS: Increased expression of MTs in the kidney with ageing might be a protective mechanism against increased oxidative stress, which is closely related to the ageing process. Our findings indicate that MTs are functionally involved in the pathophysiology of ageing-related processes.
BACKGROUND:Human lifespan is increasing continuously and about one-third of the population >70 years of age suffers from chronic kidney disease. The pathophysiology of the loss of renal function with ageing is unclear. METHODS: We determined age-associated gene expression changes in zero-hour biopsies of deceased donor kidneys without laboratory signs of impaired renal function, defined as a last serum creatinine >0.96 mg/dL in females and >1.18 mg/dL in males, using microarray technology and the Significance Analysis of Microarrays routine. Expression changes of selected genes were confirmed by quantitative polymerase chain reaction and in situ hybridization and immunohistochemistry for localization of respective mRNA and protein. Functional aspects were examined in vitro. RESULTS: Donors were classified into three age groups (<40, 40-59 and >59 years; Groups 1, 2 and 3, respectively). In Group 3 especially, genes encoding for metallothionein (MT) isoforms were more significantly expressed when compared with Group 1; localization studies revealed predominant staining in renal proximal tubular cells. RPTEC/TERT1 cells overexpressing MT2A were less susceptible towards cadmium chloride-induced cytotoxicity and hypoxia-induced apoptosis, both models for increased generation of reactive oxygen species. CONCLUSIONS: Increased expression of MTs in the kidney with ageing might be a protective mechanism against increased oxidative stress, which is closely related to the ageing process. Our findings indicate that MTs are functionally involved in the pathophysiology of ageing-related processes.
Authors: Faezeh Sarayloo; Alexandre Dionne-Laporte; Helene Catoire; Daniel Rochefort; Gabrielle Houle; Jay P Ross; Fulya Akçimen; Rachel De Barros Oliveira; Gustavo Turecki; Patrick A Dion; Guy A Rouleau Journal: PLoS One Date: 2019-11-14 Impact factor: 3.240