When injury occurs, it implies that attack has overcome defence. Tubulointerstitial injury plays important roles in acute kidney injury (AKI) and chronic kidney disease (CKD) and is the common pathway leading to end-stage renal disease, but how the renal tubulointerstitium defends against attack is poorly understood. Emerging evidence suggests that collecting ducts (CDs), which modify urine from nephrons and drain into ureter, could be key defenders protecting tubulointerstitium from injury; furthermore, the canonical renal vitamin A signalling physiologically confined to CDs could be a key regulator of this protective machinery. This hypothesis can be tested by in vitro, in vivo and clinical studies, particularly by repressing or boosting key molecular regulators in CDs, to observe the resulting phenotypes in models of AKI and CKD. Further investigation of this hypothesis could lead to new strategies for diagnosis, prevention and treatment of AKI and CKD.