Protein Disulfide Isomerase Inhibition Impairs Keap1/Nrf2 Signaling and Mitochondrial Function and Induces Apoptosis in Renal Proximal Tubular Cells.

Protein Disulfide Isomerase Inhibition Impairs Keap1/Nrf2 Signaling and Mitochondrial Function and Induces Apoptosis in Renal Proximal Tubular Cells. Am J Physiol Renal Physiol. 2020 Aug 24;: Authors: Pokkunuri ID, Lokhandwala MF, Banday AA Abstract Renal proximal tubular apoptosis plays a critical role in kidney health and disease. However, cellular molecules that trigger renal apoptosis remain elusive. Here, we evaluated the effect of inhibiting protein disulfide isomerase (PDI), a critical thioredoxin chaperone protein, on apoptosis, and the underlying mechanisms in human renal proximal tubular (HK2) cells. HK2 cells were transfected with PDI specific siRNA in the absence and presence of an antioxidant tempol. PDI siRNA transfection resulted in a decrease of ~70% in PDI protein expression and enzyme activity. PDI inhibition increased caspase-3 activity and induced profound cell apoptosis. Mitochondrial function, as assessed by mitochondrial cytochrome c levels, mitochondrial membrane potential, oxygen consumption, and ATP levels, was significantly reduced in the PDI inhibited cells. Also, PDI inhibition caused Nrf2 (nuclear factor E2 related factor 2, a redox-sensitive transcription factor) cytoplasmic sequestration, decreased superoxide dismutase, and glutathione S-transferase activities, and increased oxidative stress. In PDI inhibited cells, tempol reduced apoptosis, caspase-3 activity, and oxidative stress, and also restored N...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research