Tumour necrosis factor-alpha at the intersection of renal epithelial and immune cell function

This review explores the roles of tumour necrosis factor-alpha (TNF) in kidney physiology and pathology. TNF, produced by renal epithelial cells, regulates glucose, electrolyte, water and urea transport by modulating key transporters such as sodium-glucose co-transporter-2 (SGLT2), sodium-potassium-chloride cotransporter 2 (NKCC2), sodium chloride cotransporter (NCC), epithelial sodium channel (ENaC), aquaporin-2 (AQP2) and urea transporters. Under non-inflammatory conditions, TNF functions as a regulatory 'brake' on water and solute transport, particularly by attenuating NKCC2 and AQP2 activity. Disruption of these actions, coupled with increased salt intake, shifts mice from being salt-resistant to salt-sensitive, thereby altering their blood pressure. In autoimmune diseases, chronic kidney disease (CKD), hypertension with renal inflammation, and sepsis, TNF drives immune responses and disease progression. Although mechanisms underlying tubular epithelial cell (TEC)-immune cell interactions remain unclear, emerging evidence indicates that the spatial organization of immune responses in the kidney is associated with distinct TEC signature phenotypes. Hypertonicity- and NFAT5 (i.e. nuclear factor of activated T cells 5)-driven TNF production in TECs and T lymphocytes may influence immune cell communication by affecting co-stimulatory molecule expression and ENaC activity on macrophages and dendritic cells. Although TNF is generally pathogenic in renal diseases, its inhibition does not always confer protection because its effects on endoplasmic reticulum stress, ion transport, vascular smooth muscle and immune cells are influenced by distinct cellular sources and signalling mechanisms through TNF receptors 1 and 2. Anti-TNF therapies are crucial for treating chronic inflammatory diseases and may also aid in preventing the progression of acute kidney injury to CKD. A more complete understanding of the role of TNF in immunophysiological responses may enable the development of more targeted therapeutic strategies.