Abstract: TH-PO268

Loss of Melanocortin 5 Receptor Exacerbates Endotoxic AKI via Impairing Regulatory T Cell Response

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic


  • Xu, Yahong, Yangpu Hospital, Tongji University, Shanghai, Shanghai, China
  • Zhou, Rong, Yangpu Hospital, Tongji University, Shanghai, Shanghai, China
  • Gong, Rujun, Brown Medical School, Providence, Rhode Island, United States

Pituitary melanocortin neuropeptides, exemplified by α-melanocyte-stimulating hormone, have long been recognized to possess a remarkable renoprotective activity in diverse forms of acute kidney injury (AKI). However, the molecular mechanism responsible for this beneficial action has been illusive and exactly which type of melanocortin receptor conveys the renoprotective effect remains to be defined. Lately, there is growing evidence suggesting that melanocortin 5 receptor (MC5R) signaling confers a protective effect in multiple organ systems. The role of MC5R in kidney injury was examined in this study.


MC5R knockout mice (KO) and congenic wild-type (WT) littermates were injured with lipopolysaccharides (LPS) and AKI examined. Bone marrow derived cells were prepared from WT or KO mice and adoptively transferred to KO mice followed by LPS injury.


Mice with global knockout of MC5R were phenotypically indistinguishable from their WT littermates, and exhibited normal development with undetectable difference in kidney physiology, function and histology. As compared with WT controls, KO mice developed much severer AKI upon LPS injury, as evidenced by higher serum creatinine levels, more urinary excretion and renal expression of lipocalin-2, exacerbated renal histologic damages and tubular cell death, and amplified renal inflammation. This worsened AKI in KO mice was unlikely attributable to a tubular cell-autonomous mechanism, because primary cultures of proximal tubular epithelial cells derived from KO and WT mice demonstrated similar cellular injury and death and comparable inflammatory response following LPS injury. Instead, the amount of CD4+Foxp3+ regulatory T cells in the injured kidney from KO mice was strikingly diminished, concommitant with a drastic amplification of renal inflammatory infiltrations, thus underscoring an impaired immune tolerance to LPS injury. Moreover, adoptive transfer of bone marrow derived cells derived from congenic WT littermates to KO mice substantially replenished CD4+Foxp3+ regulatory T cells in the kidney following LPS injury, resulting in a substantial improvement of the LPS-invoked AKI and renal inflammation.


Collectively, MC5R is likely essential for regulatory T cell response to LPS injury and thereby conveys a protective activity in endotoxic AKI.