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Kidney Week

Abstract: SA-PO526

Low Expression of Autophagy-Related Protein 5 (ATG5) Leads to Suppression of Autophagy in Patients with Diabetic Nephropathy and Retinopathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Nakhoul, Rola, Szeged Faculty of Medicine, Szeged, Hungary
  • Nakhoul, Nakhoul, Baruch padeh Poriya Medical center, Lower Galilee, Israel
  • Evgeny, Farber, Baruch padeh Poriya Medical center, Lower Galilee, Israel
  • Nakhoul, Farid M., Azrieli faculty of Medicine, Lower Galilee, Israel
  • Abass, Remah, Baruch padeh Poriya Medical center, Lower Galilee, Israel
Background

Autophagy is a catabolic mechanism that involves lysosomal-dependent degradation of unnecessary or dysfunctional intracellular components, plays role in diabetic nephropathy (DN) and retinopathy (DR). ATG5 is one of the most important participants in the autophagy mechanism. Our study's aim was to investigate if aberrant expression of ATG5 protein/ Atg5 gene is associated with DN or DR.

Methods

The study included 120 human participants in 4 groups – Healthy, diabetic (DM), DN and DR; 10 mice in 2 groups – healthy and DN. Western blot analyses of ATG5 and its downstream collaborator LC3-II were performed on human white blood cell lysates and murine renal lysates. Immunohistochemical analysis was performed on mice renal tissues. qRT-PCR analysis of ATG5 was performed on total mRNA isolated from human WBC.

Results

1.ATG5 protein expression was decreased in DM patients, with and without complications [0.66 ± 0.06 A.U in DM patients (n=30) p <0.01), 0.62 ± 0.06 A.U in DN, (n=30) p<0.001), 0.67± 0.05 A.U in DR patients (n=30) p<0.01)], compared with the healthy control 0.97 ± 0.04 A.U.

2. A 2.5-fold decrease in the percentage of ATG5-stained areas in the PCT of DN mice (4.42 ± 1.08%) compared with W.T mice (10.87 ± 1.01%).
3. The expression of Atg5 gene between the groups by qRT-PCR analyses: in the DN (0.0069 ± 0.0005) and DR patients (0.0069 ± 0.0004) was down regulated at the mRNA levels, compared with healthy controls (0.0083 ± 0.0008).

4. Decreased LC3-II levels in DM patients (0.50 ± 0.04 A.U ( n=18) p < 0.001) DN patients (0.44 ± 0.05 A.U, (n=19) p < 0.001) and DR patients (0.43 ± 0.05 A.U ( n=18) p < 0.001) compared with the healthy control (0.81 ± 0.05 A.U (n=19).

5. The renal LC3-II protein expression was found to be greatly decreased in the tubules of DN mice when compared with W.T mice.

Conclusion

1.ATG5, as well as its downstream collaborator LC3-II, are down-regulated in DN & DR patients, which contributes to deficiencies in autophagy process.
2.Impairment of this process can lead to accumulation of abnormal proteins and molecules that can lead to the development and progression of DN &DR.
3.Therapeutic potential of ATG5 modulations as a novel treatment strategy for DN/DR patients through the autophagy mechanism may serve as a goal in the development of drugs for diabetic complications.

Funding

  • Government Support - Non-U.S.