Abstract: SA-PO639
Oral L-lysine Treatment Ameliorates Proximal Tubular Damage in Mice with Alport Syndrome
Session Information
- Genetic Kidney Diseases: Models, Mechanisms, and Therapies
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Ramakrishnan, Suresh K, UniversitatsKlinikum Heidelberg, Heidelberg, Baden-Württemberg, Germany
- Li, Jiayi, UniversitatsKlinikum Heidelberg, Heidelberg, Baden-Württemberg, Germany
- Rickert-Zacharias, Verena, UniversitatsKlinikum Heidelberg, Heidelberg, Baden-Württemberg, Germany
- Miner, Jeffrey H., Washington University in St Louis School of Medicine, St Louis, Missouri, United States
- Simons, Matias, UniversitatsKlinikum Heidelberg, Heidelberg, Baden-Württemberg, Germany
Background
Chronic kidney disease (CKD) is characterized by a long-term decline of kidney function. Proteinuria induced by glomerular damage is one of the hallmarks of CKD. Apart from the glomerular damage, the increased tubular load of proteins and protein-bound lipids can damage proximal tubular cells (PTC), causing tubulointerstitial fibrosis. Treatment with the basic amino acid L-lysine, which is shown to be safe in humans, has been shown to inhibit protein uptake in PTC. Therefore, we hypothesized that blocking PTC protein uptake via L-lysine might protect against tubulointerstitial damage in glomerular diseases, such as Alport syndrome.
Methods
Col4a3 Wildtype (WT) and knockout (Alport mice) in 129/Sv background were treated with and without L-lysine chloride (50mg/ml) in drinking water from 5 weeks of age for 3 weeks. Blood gas analysis and transdermal glomerular filtration rate (GFR) was measured. Kidney samples were analyzed for histology and injury markers. Induced renal epithelial cells (iRECs) grown on filters were used. Albumin-Alexa 647 uptake studies were performed upon treatment with different concentrations of L-Lysine chloride. Lipotoxic effects were studied upon treatment with albumin-bound palmitic acid.
Results
We observed a significant increase in albuminuria on day 1 of the L-Lysine treatment in both WT and Alport mice. Interestingly, there was a progressive decrease of albuminuria in L-Lysine-treated Alport male mice starting from week 1 to the end of the study. Gene expression of kidney injury and fibrosis markers were significantly ameliorated in the Alport male mice treated with L-lysine. No change in GFR was found between the groups. Albumin uptake was reduced in iRECs treated with L-lysine. We confirmed that iRECs express megalin and cubilin on the apical surface when plated on Transwell filters. L-lysine treatment significantly decreased the lipotoxicity exhibited upon addition of palmitic acid.
Conclusion
Our preliminary data suggests that oral L-Lysine treatment has beneficial effects in Alport mice. We are currently performing proteomics and metabolomics on renal cortical samples on these mice to identify the mechanisms underlying the protective effects. In the future, L-Lysine could be proposed as an efficient and safe therapeutic strategy to prevent proximal tubular damage in glomerular diseases.