Abstract
Tubulointerstitial disease in the kidney culminates in renal fibrosis that portents organ failure. Twist1, a basic helix-loop-helix protein 38 transcription factor, regulates several essential biological functions, but inappropriate Twist1 activity in the kidney epithelium can trigger kidney fibrogenesis and chronic kidney disease. By contrast, Twist1 in circulating myeloid cells may constrain inflammatory injury by attenuating cytokine generation. To dissect the effects of Twist1 in kidney tubular versus immune cells on renal inflammation following toxin-induced renal injury, we subjected mice with selective deletion of Twist1 in renal epithelial cells or macrophages to aristolochic acid-induced chronic kidney disease. Ablation of Twist1 in the distal nephron attenuated kidney damage, interstitial fibrosis, and renal inflammation after aristolochic acid exposure. However, macrophage-specific deletion of Twist1 did not impact the development of aristolochic acid-induced nephropathy. In vitro studies confirmed that Twist1 in renal tubular cells underpins their susceptibility to apoptosis and propensity to generate pro-fibrotic mediators in response to aristolochic acid. Moreover, co-culture studies revealed that Twist1 in renal epithelia augmented the recruitment and activation of pro-inflammatory CD64+ macrophages. Thus, Twist1 in the distal nephron rather than in infiltrating macrophages propagates chronic inflammation and fibrogenesis during aristolochic acid-induced nephropathy.