Cellular and metabolic effects of renin-angiotensin system blockade on glycogen storage disease type I nephropathy
Open Access
- 7 October 2021
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 31 (6), 914-928
- https://doi.org/10.1093/hmg/ddab297
Abstract
Glycogen Storage Disease Type I (GSDI) is an inherited disease caused by glucose-6 phosphatase (G6Pase) deficiency, leading to a loss of endogenous glucose production and severe hypoglycemia. Moreover, most GSDI patients develop a chronic kidney disease (CKD) due to lipid accumulation in the kidney. Similar to diabetic CKD, activation of renin-angiotensin system (RAS) promotes renal fibrosis in GSDI. Here, we investigated the physiological and molecular effects of RAS blockers in GSDI patients and mice. A retrospective analysis of renal function was performed in 21 GSDI patients treated with RAS blockers. Cellular and metabolic impacts of RAS blockade were analyzed in K.G6pc−/− mice characterized by G6pc1 deletion in kidneys. GSDI patients started RAS blocker treatment at a median age of 21 years and long-term treatment reduced the progression of CKD in about 50% of patients. However, CKD progressed to kidney failure in 20% of treated patients, requiring renal transplantation. In K.G6pc−/− mice, CKD was associated with an impairment of autophagy and ER stress. RAS blockade resulted in a rescue of autophagy and decreased ER stress, concomitantly with decreased fibrosis and improved renal function, but without impact on glycogen and lipid contents. In conclusion, these data confirm the partial beneficial effect of RAS blockers in the prevention of CKD in GSDI. Mechanistically, we show that these effects are linked to a reduction of cell stress, without affecting metabolism.This publication has 33 references indexed in Scilit:
- Comparative effectiveness of renin-angiotensin system blockers and other antihypertensive drugs in patients with diabetes: systematic review and bayesian network meta-analysisBMJ, 2013
- Endoplasmic reticulum stress as a pro-fibrotic stimulusBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2013
- Mechanisms and Treatment of CKDJournal of the American Society of Nephrology, 2012
- KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 UpdateAmerican Journal of Kidney Diseases, 2012
- Comparison of Stain-Free gels with traditional immunoblot loading control methodologyAnalytical Biochemistry, 2012
- Renal Function in Glycogen Storage Disease Type I, Natural Course, and Renopreservative Effects of ACE InhibitionClinical Journal of the American Society of Nephrology, 2009
- Efficacy of ACE-inhibitor therapy on renal disease in glycogen storage disease type 1: a multicentre retrospective studyClinical Endocrinology, 2005
- Glycogen storage disease type I: diagnosis, management, clinical course and outcome. Results of the European study on glycogen storage disease type I (ESGSD I)European Journal of Pediatrics, 2002
- Glycogen storage disease type I: indications for liver and/or kidney transplantationEuropean Journal of Pediatrics, 2002
- Glycogen storage disease type I: diagnosis, management, clinical course and outcome. Results of the European Study on Glycogen Storage Disease Type I (ESGSD I)European Journal of Pediatrics, 2002