Periodic Reporting for period 2 - RENOPROTECT (Targeting tubular reabsorption for kidney protection)
Período documentado: 2022-07-01 hasta 2023-12-31
To address this hypothesis, we will first study mechanisms of cubilin-mediated protein uptake in a humanized Drosophila model. Second, we will explore monoallelic CUBN expression and partial cryptic exon inclusion as two possible genetic mechanisms by which heterozygosity at the CUBN locus could promote proximal tubule fitness and tissue repair under different protein and lipid overload conditions. The final objective is to identify strategies to block tubular protein in conditions with glomerular proteinuria. Apart from genetic manipulations, this will include a novel nanoparticle delivery method. Altogether, our integrative translational approach will combine human genetics and experimental studies to explore a new mechanism of proximal tubule homeostasis that may also be applicable to other tissues. Our goal is to establish a novel paradigm for kidney protection with high relevance for the diagnosis, prognosis and treatment of kidney disease.
Finally, we explored whether the combination of glomerular albuminuria and dyslipidemia could cause lipotoxic effects in the proximal tubules, as albumin might function as a vector for intracellular delivery of damaging fatty acids. For this, we treated a diabetic mouse model with a high fat diet. Interestingly, excess fat exposure caused injury in renal proximal tubular cells (PTCs), but only in those cells that could not store fat in lipid droplets. Mechanistically, we identified stress in the endoplasmic reticulum (ER) as the main cause of proximal tubular injury. ER stress was caused by elevated levels of saturated triacylglycerol precursors, reduced lipid droplet formation and, consequently, decreased membrane fluidity in the ER. The addition of monounsaturated fatty acid rescued the cytotoxic effects by normalizing membrane order and by increasing both triacylglycerol and lipid droplet formation. These results were recently published in eLife (Perez-Marti et al, 2022), emphasizing the importance of monounsaturated fatty acids for the dietary management of diabetic kidney disease by preventing lipid bilayer stress in the ER and promoting triacylglycerol and lipid droplet formation in PTCs.