Role of peroxisomal biogenesis in proximal tubular epithelial cells subjected to stress

• Grant number: 24/18100-6
• Support Opportunities: Scholarships in Brazil - Program to Stimulate Scientific Vocations
• Start date: January 06, 2025
• End date: February 20, 2025
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Niels Olsen Saraiva Câmara
• Grantee: Benedito dos Santos Alves
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Diabetic kidney disease (DKD) is a serious microvascular complication that develops in patients with type 1 (T1D) or type 2 (T2D) diabetes and may be related to the prevalence of end-stage renal disease, which requires dialysis or renal replacement therapy. In DKD, the proximal tubular epithelial cells (PTECs), due to excess sodium and glucose in the filtrate, present a more pronounced O2 consumption, which contributes to increased activity of the Na+/K+ ATPase (NKA) pump. NKA activity is driven by adenosine triphosphate (ATP) molecules, which are produced by oxidative phosphorylation in mitochondria, an O2-dependent process. Physiologically, the main source of ATP for PTECs is mitochondrial fatty acid (FA) beta-oxidation. In DKD, the high FA supply to PTECs causes increased mitochondrial oxidative stress and energy deficit. Peroxisomes work together with mitochondria through the beta-oxidation of very long-chain FA, providing mitochondria with short- and medium-chain FA, which are oxidized to acetyl-coenzyme A. Thus, disturbances in the beta-oxidation of FA in peroxisomes may contribute to the cellular accumulation of unmetabolized FA. According to data in the literature, high levels of free FA can inhibit the activity of the Na+/K+ ATPase pump, interfere with the mitochondrial membrane potential and induce an inflammatory response in PTECs subjected to hypoxia and reoxygenation. For peroxisomes to function fully, they require proteins called peroxins (PEX), which are related to their protein import machinery and are involved in the biogenesis of peroxisomes, acting in the formation of the peroxisomal membrane, compartmentalization of peroxisomal matrix proteins and peroxisome proliferation. Among the peroxins, PEX16 stands out due to its role, in combination with other peroxins, in the insertion of peroxisomal membrane proteins (PMPs), which act in the transport of very long-chain FA into peroxisomes. Mutations in the PEX16 gene are associated with disruptions in peroxisome assembly and detrimental accumulation of very long-chain fatty acids, long-chain saturated and polyunsaturated fatty acids (VLC-PUFAs) and branched-chain fatty acids. Lipid accumulation in renal cells has been associated with the triggering of signals involved in inflammation, oxidative stress and cell death, events implicated in the development of DKD. Thus, this study aims to evaluate the hypothesis that peroxisome dysfunction is involved in the pathogenesis of proximal tubular injury in mice with type 1 diabetes. (AU)