Abstract
Lipotoxicity-induced mesangial cell apoptosis is implicated in the exacerbation of diabetic nephropathy (DN). Protein arginine methyltransferases (PRMTs) have been known to regulate a variety of biological functions. Recently, it was reported that PRMT1 expression is increased in proximal tubule cells under diabetic conditions. However, their roles in mesangial cells remain unexplored. Thus, we examined the pathophysiological roles of PRMTs in mesangial cell apoptosis. Treatment with palmitate, which mimics cellular lipotoxicity, induced mesangial cell apoptosis via protein kinase RNA-like endoplasmic reticulum kinase (PERK) and ATF6-mediated endoplasmic reticulum (ER) stress signaling. Palmitate treatment increased PRMT1 expression and activity in mesangial cells as well. Moreover, palmitate-induced ER stress activation and mesangial cell apoptosis was diminished by PRMT1 knockdown. In the mice study, high fat diet-induced glomerular apoptosis was attenuated in PRMT1 haploinsufficient mice. Together, these results provide evidence that lipotoxicity-induced PRMT1 expression promotes ER stress-mediated mesangial cell apoptosis. Strategies to regulate PRMT1 expression or activity could be used to prevent the exacerbation of DN.
Highlights
Diabetic nephropathy (DN), one of the main causes of chronic kidney disease, is developed by 30–40% of diabetic patients, making it one of the most common complications of diabetes [1]
To confirm whether endoplasmic reticulum (ER) stress signaling activation is linked to mesangial cell apoptosis, mesangial cells were treated with thapsigargin, which triggers ER stress by inhibiting sarcoplasmic/ER Ca2+-ATPase (SERCA), leading to Ca2+ depletion
These results suggest that lipotoxicity induces mesangial cell apoptosis via protein kinase RNA-like endoplasmic reticulum kinase (PERK) and activating transcription factor 6 (ATF6) signaling pathways
Summary
Diabetic nephropathy (DN), one of the main causes of chronic kidney disease, is developed by 30–40% of diabetic patients, making it one of the most common complications of diabetes [1]. It is known that mesangial cells are susceptible to lipotoxicity, and lipotoxicity-induced apoptosis of mesangial cells has been implicated in the development of renal failure [8,9]. ER stress has been implicated in mediating lipotoxicity-induced apoptosis in multiple cell types, including renal proximal cells [10,11]. Increased PRMT1 expression in proximal tubule cells has been reported to be critical to the progression of diabetic nephropathy [14]. In this study, we have subjected cultured rat mesangial cells to a palmitate challenge and fed a high fat diet to mice to induce lipotoxicity in order to elucidate the role of PRMTs in lipotoxicity-induced mesangial cell apoptosis and the pathogenesis of diabetic nephropathy
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
