Alteration in Rab11‐mediated endocytic trafficking of LDL receptor contributes to angiotensin II‐induced cholesterol accumulation and injury in podocytes

Abstract

Objectives: Exposure of podocytes to angiotensin II (Ang II) enhances the abundance of the cell surface glycoprotein, low-density lipoprotein receptor (LDLR) and promotes significant changes in the cellular cholesterol content. Recent investigation provides evidence that the small GTPase Rab11 is involved in the regulation of LDLR, but the exact mechanisms remain unknown. In this study, the role of Rab11 in posttranscriptional regulation of LDLR was evaluated to investigate potential mechanisms of podocyte cholesterol dysregulation in chronic kidney disease. Materials and Methods: Cholesterol content, LDLR and Rab11 expression were assessed in podocytes from Ang II-infused mice. In vitro, the intracellular localization of LDLR was detected under different conditions. Rab11 expression was modulated and we then explored the effect of anti-lipid cytotoxicity by detecting LDLR expression and trafficking, cholesterol content and apoptosis in podocytes. Results: Cholesterol accumulation, upregulated expression of LDLR and Rab11 were discovered in podocytes from Ang II-infused mice. Ang II enhanced the co-precipitation of LDLR with Rab11 and accelerated the endocytic recycling of LDLR to the plasma membrane. Additionally, silencing Rab11 promoted lysosomal degradation of LDLR and alleviated Ang II-induced cholesterol accumulation and apoptosis in podocytes. Conversely, overexpression of Rab11 or inhibition of lysosomal degradation up-regulated the abundance of LDLR and aggravated podocyte cholesterol deposition. Conclusions: Rab11 triggers the endocytic trafficking and recycling of LDLR; overactivation of this pathway contributes to Ang II-induced podocyte cholesterol accumulation and injury. | INTRODUCTIONThe precise architecture of podocytes takes part in maintaining the selective permeability of the glomerular filtration barrier. For several Jijia Hu and Zijing Zhu contributed equally to this work.

LRH‐1 activation alleviates diabetes‐induced podocyte injury by promoting GLS2‐mediated glutaminolysis

“…Conditionally immortalized human podocytes (HPCs) cell line was obtained from Dr. Moin A. Saleem (Academic Renal Unit, Southmead Hospital, Bristol, UK). HPCs were grown as described previously 16 . Briefly, HPCs were cultured in RPMI‐1640 basal medium (glucose 5.5 mM, HyClone, USA) containing 10% heat‐inactivated fetal bovine serum (FBS; Gibco, USA), penicillin G (100 IU/mL), streptomycin (100 mg/mL) and 1× insulin‐transferrin‐selenium (ITS; Invitrogen, USA) at 33°C for proliferation; then they were thermoswitched to 37°C for 10–14 days without ITS to induce differentiation.…”

“…HPCs were grown as described previously. 16 Briefly, HPCs were cultured in RPMI-1640 basal medium (glucose 5.5 mM, HyClone, USA) containing 10% heat-inactivated fetal bovine serum (FBS; Gibco, USA), penicillin G (100 IU/mL), streptomycin (100 mg/mL) and 1Â insulin-transferrin-selenium (ITS; Invitrogen, USA) at 33 C for proliferation; then they were thermoswitched to 37 C for 10-14 days without ITS to induce differentiation. All experiments were performed with differentiated cells.…”

The relationship between cholesterol metabolism and mitochondrial function in chronic obstructive pulmonary diseases

“…High cholesterol levels are considered as a risk factor for atherosclerosis but are also closely related to other diseases, such as chronic kidney disease, osteoporosis, diabetes mellitus and lung diseases. [23][24][25][26] Recent studies have demonstrated that cholesterol plays an important role in pulmonary diseases. 17 In lung cancer, cancer tissues contain more free cholesterol and cholesterol ester than para-cancer tissues.…”

“…Different processes of cholesterol metabolism are regulated by different factors in diseases. High cholesterol levels are considered as a risk factor for atherosclerosis but are also closely related to other diseases, such as chronic kidney disease, osteoporosis, diabetes mellitus and lung diseases 23–26 . Recent studies have demonstrated that cholesterol plays an important role in pulmonary diseases 17 .…”