Joseph M Garagliano1, Akemi Katsurada1, Kayoko Miyata1, Andrei V Derbenev1, Andrea Zsombok1, L Gabriel Navar1, Ryousuke Satou2. 1. Department of Physiology and Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Louisiana. 2. Department of Physiology and Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Louisiana. Electronic address: rsato@tulane.edu.
Abstract
BACKGROUND: Elevated advanced glycation end products (AGE) in diabetes mellitus (DM) are implicated in the progression of DM-associated tissue injury, including diabetic nephropathy. The intrarenal renin-angiotensin system, in particular augmentation of angiotensinogen (AGT) in proximal tubular cells (PTC), plays a crucial role in the development of diabetic nephropathy. This study investigated hypothesis that AGE stimulates AGT production in PTC. MATERIALS AND METHODS: Urinary AGT and AGE levels in streptozotocin-induced DM mice were measured by enzyme-linked immunosorbent assays. AGT expression and secretion were evaluated in cultured rat PTC receiving 0-200 µg/ml AGE-BSA treatments for 24 hours. Furthermore, intracellular signaling pathways activated by AGE were elucidated. RESULTS: DM mice exhibited greater urinary AGT and AGE levels compared to control mice (AGT: 21.6 ± 5.5 ng/day vs. 190.1 ± 57.8 ng/day, AGE: 139.1 ± 21.6 μg/day vs. 332.8 ± 102.7 μg/day). In cultured PTC, treatment with AGE-BSA enhanced AGT mRNA expression (3.43 ± 0.11-fold compared to control), intracellular AGT protein levels (3.60 ± 0.38-fold), and secreted AGT levels (2.11 ± 0.18-fold). On the other hand, AGT levels were not altered in PTC receiving nonglycated BSA. Recombinant soluble AGE receptor, which competes with endogenous AGE receptor, diminished the AGE-induced AGT upregulation, suggesting that AGE-BSA stimulates AGT expression via activation of the AGE receptor. Enhanced phosphorylation of ERK1/2 and c-Jun, but not p38 MAP kinase, were observed in AGE-BSA-treated PTC. AGE-induced AGT augmentation was attenuated by an ERK inhibitor. CONCLUSIONS: The findings indicate that AGE enhances proximal tubular AGT expression via ERK1/2, which can exacerbate the development of diabetic related kidney injury.
BACKGROUND: Elevated advanced glycation end products (AGE) in diabetes mellitus (DM) are implicated in the progression of DM-associated tissue injury, including diabetic nephropathy. The intrarenal renin-angiotensin system, in particular augmentation of angiotensinogen (AGT) in proximal tubular cells (PTC), plays a crucial role in the development of diabetic nephropathy. This study investigated hypothesis that AGE stimulates AGT production in PTC. MATERIALS AND METHODS: Urinary AGT and AGE levels in streptozotocin-induced DMmice were measured by enzyme-linked immunosorbent assays. AGT expression and secretion were evaluated in cultured rat PTC receiving 0-200 µg/ml AGE-BSA treatments for 24 hours. Furthermore, intracellular signaling pathways activated by AGE were elucidated. RESULTS:DMmice exhibited greater urinary AGT and AGE levels compared to control mice (AGT: 21.6 ± 5.5 ng/day vs. 190.1 ± 57.8 ng/day, AGE: 139.1 ± 21.6 μg/day vs. 332.8 ± 102.7 μg/day). In cultured PTC, treatment with AGE-BSA enhanced AGT mRNA expression (3.43 ± 0.11-fold compared to control), intracellular AGT protein levels (3.60 ± 0.38-fold), and secreted AGT levels (2.11 ± 0.18-fold). On the other hand, AGT levels were not altered in PTC receiving nonglycated BSA. Recombinant soluble AGE receptor, which competes with endogenous AGE receptor, diminished the AGE-induced AGT upregulation, suggesting that AGE-BSA stimulates AGT expression via activation of the AGE receptor. Enhanced phosphorylation of ERK1/2 and c-Jun, but not p38 MAP kinase, were observed in AGE-BSA-treated PTC. AGE-induced AGT augmentation was attenuated by an ERK inhibitor. CONCLUSIONS: The findings indicate that AGE enhances proximal tubular AGT expression via ERK1/2, which can exacerbate the development of diabetic related kidney injury.
Authors: Tusty-Jiuan Hsieh; Pierre Fustier; Chih-Chang Wei; Shao-Ling Zhang; Janos G Filep; Shiow-Shiu Tang; Julie R Ingelfinger; I George Fantus; Pavel Hamet; John S D Chan Journal: J Endocrinol Date: 2004-12 Impact factor: 4.286
Authors: Y Yamamoto; I Kato; T Doi; H Yonekura; S Ohashi; M Takeuchi; T Watanabe; S Yamagishi; S Sakurai; S Takasawa; H Okamoto; H Yamamoto Journal: J Clin Invest Date: 2001-07 Impact factor: 14.808
Authors: Thoralf M Wendt; Nozomu Tanji; Jiancheng Guo; Thomas R Kislinger; Wu Qu; Yan Lu; Loredana G Bucciarelli; Ling Ling Rong; Bernhard Moser; Glen S Markowitz; Gunther Stein; Angelika Bierhaus; Birgit Liliensiek; Bernd Arnold; Peter P Nawroth; David M Stern; Vivette D D'Agati; Ann Marie Schmidt Journal: Am J Pathol Date: 2003-04 Impact factor: 4.307
Authors: Harish Shankaran; Danielle L Ippolito; William B Chrisler; Haluk Resat; Nikki Bollinger; Lee K Opresko; H Steven Wiley Journal: Mol Syst Biol Date: 2009-12-01 Impact factor: 11.429
Authors: Ryousuke Satou; Michael W Cypress; T Cooper Woods; Akemi Katsurada; Courtney M Dugas; Vivian A Fonseca; L Gabriel Navar Journal: Am J Physiol Renal Physiol Date: 2019-11-04
Authors: Venkateswara R Gogulamudi; Danielle Y Arita; Camille R T Bourgeois; Justine Jorgensen; Jing He; William C Wimley; Ryosuke Satou; Alexis A Gonzalez; Minolfa C Prieto Journal: Sci Rep Date: 2021-07-05 Impact factor: 4.379