Macula Densa Alleviates Shiga Toxin-Induced Acute Kidney Injury via CCN1-Mediated Renal Tubular Repair

Shiga toxins (Stx), produced by Shiga toxin-producing <i>Escherichia coli</i>, preferentially attack renal tissue and frequently induce acute kidney injury (AKI) and renal failure. To prevent irreversible damage, the injured renal tissue, particularly renal tubular epithelium, mounts a remodeling and regeneration response to repair itself. However, how such intrinsic renal repair processes are initiated and coordinated in infected renal tubular regions remains elusive. Herein, we reported that macula densa apparatus, in addition to its conventional role as a salt sensor in nephron, can function as an endogenous sensor for exogenous toxins (e.g., Stx). We demonstrated that macula densa cells orchestrate a rapid repair niche by initiating transcriptional activation of repair and regeneration factors in both Stx-injured murine models and human kidney organoids. Mechanistically, we showed that in response to Stx exposure, macula densa cells release a specific repair factor CCN1, which effectively promotes the regeneration of toxin-injured renal tubular epithelium and facilitates renal tubular repair through integrin-mediated signaling pathways. Moreover, we demonstrated that treatment with recombinant CCN1 can greatly ameliorate the structural damage and significantly restore the proximal tubular reabsorption capacity in Stx-infected kidney organoids. Our finding highlights a novel role of macula densa apparatus in toxin-induced renal injury, and paves a new avenue for treatment of AKI-associated renal diseases.