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.
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http://dx.doi.org/10.1093/hmg/ddab297 | DOI Listing |
J Pediatr Gastroenterol Nutr
November 2024
Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
Objective: Glycogen storage disorders (GSD), inherent disorders of carbohydrate metabolism, feature hypoglycemia as a hallmark. Normoglycemia and glucose monitoring are pivotal in disease management. Conventional glucometer-based monitoring may overlook hypoglycemic trends.
View Article and Find Full Text PDFNutrients
September 2024
Division of Medical Genetics, Department of Pediatrics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston), Children's Memorial Hermann Hospital, Houston, TX 77030, USA.
J Lipid Res
October 2024
Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy; CEINGE Biotecnologie Avanzate s.c.ar.l., Naples, Italy. Electronic address:
BMC Med Genomics
May 2024
Department of Pathology, West China Hospital, Sichuan University, Chengdu, 610000, China.
Cureus
October 2023
Department of Pediatrics, Faculty of Medicine and Pharmacy of Oujda, Mohammed First University, Oujda, MAR.
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