Key Points:
Proximal tubular TNF aggravates kidney injury and fibrogenesis in aristolochic acid nephropathy.
Tubular TNF disrupts the cell cycle in injured tubular epithelial cells.
TNF-mediated toxic renal injury is independent of systemic immune responses.
Background: Aristolochic acid nephropathy (AAN) presents with tubular epithelial cell (TEC) damage and tubulointerstitial inflammation. Although TNF-α regulates cell apoptosis and inflammatory responses, the effects of tubular TNF in the progression of AAN require elucidation.
Methods: Floxed TNF mice on the 129/SvEv background were crossed with PEPCK-Cre mice to generate PEPCK-Cre+TNFflox/flox (TNF PTKO) mice or bred with Ksp-Cre mice to generate KSP-Cre+TNFflox/flox (TNF DNKO) mice. TNF PTKO, TNF DNKO, and wild-type controls (Cre negative littermates) were subjected to acute and chronic AAN.
Results: Deletion of TNF in the proximal but not distal nephron attenuated kidney injury, renal inflammation, and tubulointerstitial fibrosis after acute or chronic aristolochic acid (AA) exposure. The TNF PTKO mice did not have altered numbers of infiltrating myeloid cells in AAN kidneys. Nevertheless, kidneys from AA-treated TNF PTKO mice had reduced levels of proteins involved in regulated cell death, higher proportions of TECs in the G0/G1 phase, and reduced TEC proportions in the G2/M phase. Pifithrin-α, which restores the cell cycle, abrogated differences between the wild-type and PTKO cohorts in G2/M phase arrest of TECs and kidney fibrosis after AA exposure.
Conclusions: TNF from the proximal but not the distal nephron propagates kidney injury and fibrogenesis in AAN in part by inducing G2/M cell cycle arrest of TECs.