Fig. 4

Possible proximal tubule epithelial cell signals in glomerulonephritis and renal cell carcinoma. (1) Low levels of calcium induce the release of parathyroid hormone (PTH) from parathyroid glands and this stimulates renal CYP27B1 expression. (2) 25(OH)D₃, formed in the liver, is hydroxylated by CYP27B1 to form the active metabolite, 1α-25(OH)₂D₃. (3) CYP24A1 catalyzes the conversion of 25(OH)D₃ and 1α-25(OH)₂D₃ into 24-hydroxylated products targeted for excretion. (4) Elevated levels of 1α-25(OH)₂D₃ induce the production of fibroblast growth factor-23 (FGF-23), which suppresses CYP27B1 transcription. (5) 1α-25(OH)₂D₃ may antagonize PAMP/DAMP-induced inflammasome activation. (6) Vitamin D response elements (VDRE) in the PD-L1 gene may be functionally active in the renal epithelium. (7) PAMPs/DAMPs, ROS, and IL-1β activate PD-L1 transcription factors, HIF-1α and NF-kB. PD-L1 expression can be blocked with monoclonal antibodies. (8) 1α-25(OH)₂D₃ antagonizes Akt and the transcription factor STAT3 that may be induced by IL-6 and mTORC2. IL-6 receptor monoclonal antibodies block IL-6 signals. (9) Hypoxia promotes the stability and activation of HIF-1α and HIF-2α. Both mTORC1 and mTORC2 are involved in HIF-1α regulation. mTORC2 regulates the expression of HIF-2α and is activated by VEGF cell signals. Tyrosine kinase inhibitors block VEGF receptor signals. (10) HIF-1α and HIF-2α induce the production of SDF-1 and VEGF. Antibodies that bind circulating VEGF block VEGF binding to its receptor. (11) Metformin-induced AMPK promotes PD-L1 phosphorylation and degradation. AMPK is also involved the phosphorylation of PGC-1α, which is additionally de-acetylated by sirtuins (SIRT1) during mitochondrial biogenesis and under conditions of normoxia. (12) Uric acid is a DAMP involved in the activation of the inflammasome and proximal tubule epithelial cell production of adiponectin. (13) Metformin and AICAR activate AMPK. Metformin therapy may induce the production of adiponectin. (14) γ-glutamyltransferase activity degrades glutathione (GSH) into its individual amino acids. (15) Reduced GSH scavenges free radicals and generates an oxidized form of GSH (GSSG). (16) GSH metabolism is associated with the activation of the pentose phosphate pathway. (17) NF-kB is antagonized by glucocorticoids and promotes the production of chemokines and ROS. (18) The cell signals that occur in response to PD-L1 ligation or blockade are not well characterized