Abstract: TH-PO412

Therapeutic Targeting of Melanocortin 5 Receptor: A Novel Approach for Protection against AKI

Session Information

Category: Nutrition, Inflammation, and Metabolism

  • 1401 Nutrition, Inflammation, Metabolism

Authors

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

Melanocortin peptides belong to a neuroimmunoendocrine hormone system that sustains the homeostasis of diverse organ systems. Burgeoning evidence suggests that activation of melanocortin 5 receptor (MC5R) by melanocortin neuropeptides plays a pivotal role in immunoregulation and confers a protective effect in various disease models. Nevertheless, how therapeutic targeting of MC5R affects kidney injury was unknown and explored here.

Methods

Mice were treated with MC5A, a highly selective agonist of MC5R, or with PG20N, a highly selective antagonist, prior to folic acid injury. In vitro, primary renal proximal tubular cells (PTC) were injured with tumor necrosis factor (TNF) after MC5A or PG20N treatment. Kidney or cellular injuries were assessed.

Results

Selective activation of MC5R by MC5A strikingly improved the folic acid-elicited acute kidney injury (AKI), as evidenced by a mitigated elevation of serum creatinine, reduced urinary excretion and renal expression of lipocalin-2, diminished tubular damages and tubular cell death, and attenuated renal inflammation. Conversely, selective blockade of MC5R by PG20N exacerbated the folic acid induced AKI. In normal kidney tubulointerstitium, MC5R was sporadically expressed by some renal interstitial cells but absent from renal tubules, as demonstrated by immunohistochemistry, thus underscoring a possible non-tubular cell autonomous effect of MC5R on regulating kidney injury. In support of this, in primary renal PTC, the TNF-instigated apoptosis and production of proinflammatory cytokines, like CCL2, were barely altered by MC5A or PG20N. Rather, inflammatory infiltrations in the folic acid-injured kidney, as probed by CD45 staining, was mitigated by MC5A but amplified following PG20N treatment. In parallel, CD11b+Gr-1+ myeloid-derived suppressor cells (MDSC), which have been shown to mediate a renoprotective tolerogenic response in various types of AKI, were prominently expanded after MC5A treatment but remarkably diminished by PG20N in the injured kidney. Moreover, the kidney protective effect of adoptive transfer of MDSC in folic acid-injured mice was reinforced by MC5A pretreatment of MDSC, but blunted by PG20N, thus denoting a direct modifying effect of MC5R on MDSC.

Conclusion

Altogether, therapeutic targeting of MC5R protects against folic acid AKI likely via modulating the tolerogenic MDSC response.

Funding

  • NIDDK Support