Albumin evokes Ca2+-induced cell oxidative stress and apoptosis through TRPM2 channel in renal collecting duct cells reduced by curcumin

Abstract

In proteinuric nephropathies of chronic kidney disease, the epithelial cells of the nephron including the collecting duct are exposed to high concentrations of luminal albumin. Albumin is taken up from collecting duct cells by endocytosis causing excessive reactive oxygen species (ROS) production and a proinflammatory response. Curcumin used in the traditional medicine possesses anti-inflammatory and antioxidant effects. ROS and ADP-ribose (ADPR) activate the cation channel TRPM2. We hypothesize, that albumin-induced cell stress and proinflammatory response are mediated by Ca²⁺ and can be reduced by curcumin. The cortical collecting duct (CCD) cells mpkCCD_c14 exhibit spontaneous and inducible Ca²⁺ oscillations, which can be blocked by pre-treatment with curcumin. Curcumin accumulates in plasma membrane and intracellular vesicles, where it interferes with TRPM2 and decreases the influx of Ca²⁺. Albumin reduces cell viability and increases apoptosis, NF-κB activation, and mitochondrial membrane depolarization via Ca²⁺-dependent signaling, which results in increased ROS production. Albumin-induced cell stress is diminished by the inhibition of TRPM2 after administration of curcumin and ADPR (PARP1) inhibitors. Curcumin did not reduce the Ca2+ elevation induced by thapsigargin in Ca²⁺-free medium, but it reduced the function of store-operated Ca²⁺ channels and ATP-evoked Ca²⁺ response. In conclusion, albumin-induced oxidative stress is mediated by Ca²⁺-dependent signaling via TRPM2 and leads to cell damage and a proinflammatory response, strengthening the role of CCD cells in the progression of chronic kidney disease.