Abstract: FR-PO0194
Targeting RNF145 in Renal Proximal Tubular Cells Protects Against Lipotoxicity in Diabetes
Session Information
- Diabetic Kidney Disease: Metabolic, Mitochondrial, and Inflammatory Mechanisms
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Cardiovascular-Kidney-Metabolic Health
- 601 Cardiovascular-Kidney-Metabolic Health: Basic
Authors
- Hipp, Lena, Universitat Heidelberg Medizinische Fakultat Heidelberg, Heidelberg, BW, Germany
- Loza Valdes, Angel, Universitat Heidelberg Medizinische Fakultat Heidelberg, Heidelberg, BW, Germany
- Ramakrishnan, Suresh K, Universitat Heidelberg Medizinische Fakultat Heidelberg, Heidelberg, BW, Germany
- Dibra, Indira, Universitat Heidelberg Medizinische Fakultat Heidelberg, Heidelberg, BW, Germany
- Simons, Matias, Universitat Heidelberg Medizinische Fakultat Heidelberg, Heidelberg, BW, Germany
Background
In diabetic patients, dyslipidemia drives ectopic lipid accumulation and lipotoxicity, thereby contributing to organ damage such as in diabetic kidney disease. Using induced renal epithelial cells (iRECs) and a diabetic mouse model, we previously found that monounsaturated fatty acids (FAs) caused more lipid storage in lipid droplets (LDs), but less tubular damage than the saturated palmitic acid (PA). Mechanistically, PA reduced LD formation, thereby causing the accumulation of saturated triacylglyceride (TAG) precursors in the membrane of the endoplasmic reticulum (ER), a decrease in membrane fluidity and induction of ER stress (Perez-Marti et al, 2022).
Methods
RNF145 was silenced with CRISPR/Cas9 in iRECs and subjected to the albumin-bound fatty acids palmitate (PA) and oleate (OA). Multi-Omics analysis included RNA-sequencing, proteomics, lipidomics and acyl-carnitine measurements. Seahorse and Resipher experiments were performed for metabolic analysis. Global Rnf145 KO in mice was generated with tamoxifen-inducible Rosa26-Cre at ten weeks, followed by high fat diet (enriched with saturated fat) treatment and streptozotocin (STZ) injections for sixteen weeks.
Results
Using RNA-sequencing, we identified ring-finger protein 145 (RNF145), an ER-resident E3-ubiquitin ligase, to be regulated by FA saturation in iRECs. RNF145 mRNA and protein was downregulated by PA and upregulated by OA. Interestingly, RNF145 depletion protected against PA-mediated cytotoxicity and ER-stress. Lipidomics revealed reduced accumulation of saturated TAG precursors, but increased incorporation of saturated FAs into cholesteryl esters in RNF145-KO cells. Moreover, RNF145 KO cells showed higher capacity for oxygen consumption and beta-oxidation. The stabilization of the RNF145 substrate adiponectin receptor 2 (ADIPOR2) in these cells was associated with a mild AMPK activation, likely contributing to the mitochondrial FA oxidation. Rnf145 KO mice showed overall good survival under the HFD-STZ regiment with stabilization of ADIPOR2 in several tissues.
Conclusion
Overall, RNF145 serves as a key regulator of lipid homeostasis and membrane fluidity, representing a promising target to limit lipotoxicity in renal proximal tubule cells.
Funding
- Government Support – Non-U.S.