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Abstract: PO0652

Blocking the ACE N-Domain Prevents Salt Sensitivity in Diabetes

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Veiras, Luciana C., Cedars-Sinai Medical Center, Los Angeles, California, United States
  • Bernstein, Ellen A., Cedars-Sinai Medical Center, Los Angeles, California, United States
  • Bernstein, Kenneth E., Cedars-Sinai Medical Center, Los Angeles, California, United States
  • Giani, Jorge F., Cedars-Sinai Medical Center, Los Angeles, California, United States
Background

Angiotensin converting enzyme (ACE) can regulate inflammation independently of angiotensin II production. Specifically, blocking the ACE N-domain results in the accumulation of the anti-inflammatory peptide AcSDKP. We showed that interleukin-6 (IL-6) induces salt sensitivity through an upregulation of the epithelial sodium channel (ENaC) in diabetic mice. Here, we hypothesize that blocking the ACE N-domain reduces renal IL-6 levels and prevents salt sensitivity in diabetes.

Methods

7-mo-old diabetic db/db mice lacking a functional ACE N-domain (db-nko) and db/db controls (db) were exposed to a high salt diet (HS, NaCl 4%w/w) for 4 weeks (n=6).

Results

Despite similar hyperglycemia and body weight, after HS, db-nko displayed lower mean arterial pressure (MAP) (107±5 vs. 123±4 mmHg, P<0.01), less expression of αENaC subunit (0.8±0.3 vs. 1.4±0.3 A.U., P<0.05), and lower renal IL-6 levels (112±16 vs. 270±17 pg/mg kidney, P<0.01) compared to db mice. Flow cytometry analysis of renal macrophages showed that db-nko mice have lower M1 (CD45+F4/80+CD80+) to M2 (CD45+F4/80+CD206+) ratio compared to db (2.4±0.6 vs. 4.8±0.7, P<0.05). Further, renal macrophages (3x104) were isolated by flow cytometry cell sorting, cultured for 16h, and IL-6 assessed in the culture media by ELISA. Macrophages from db-nko release significantly less IL-6 compared to db macrophages (2±1 vs. 7±2 pg/ml, P<0.01). To evaluate the role of AcSDKP, an additional group of db-nko were treated for 8 weeks with S17092, an inhibitor of prolyl-oligopeptidase that forms AcSDKP. After HS, MAP, renal αENaC expression, IL-6, and the macrophage M1/M2 ratio of db-nko+S17092 were similar to db mice. Finally, to evaluate whether the absence of the ACE N-domain affects immune or non-immune renal cells, db mice were transplanted with a bone marrow (BM) of db-nko while db-nko received a db BM. Strikingly, db-nko with db BM developed salt sensitivity but db with db-nko BM remained salt resistant (MAP after HS: 121±8 vs. 107±4 mmHg, P<0.05). The absence of salt sensitivity in db with db-nko BM was associated with less IL-6 levels and lower M1/M2 macrophage ratio in the kidney.

Conclusion

Thus, blocking the ACE N-domain and the consequent AcSDKP accumulation in immune cells, polarize macrophages towards an M2 phenotype resulting in less renal inflammation and no salt sensitivity in diabetes.

Funding

  • Other NIH Support