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Kidney Week

Abstract: FR-OR112

Notch Signaling Proteins as Key Factor in the Progression to ESRD in Diabetes

Session Information

Category: Diabetic Kidney Disease

  • 602 Diabetic Kidney Disease: Clinical

Authors

  • Kobayashi, Hiroki, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, United States
  • Satake, Eiichiro, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, United States
  • Md Dom, Zaipul I, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, United States
  • Krolewski, Andrzej S., Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, United States
Background

It has been reported that Notch signaling proteins might regulate interstitial fibrosis development in the kidneys of mice and humans. The objective of this study was to investigate an association of circulating Notch signaling proteins on the development of ESRD in subjects with diabetes during long-term follow-up.

Methods

Using the modified aptamer-based SomaScan platform, 4 proteins including Notch1, delta like protein 1 (DLL1), delta like protein 4 (DLL4), and Jagged 1 protein (JAG1) were measured in baseline plasma specimens obtained from 363 Caucasian subjects with diabetes and CKD stage 3 (CKD3); including 219 with Type 1 diabetes (T1D) and 144 with Type 2 diabetes (T2D). Additionally, the 4 proteins were also measured in 190 T1D patients with CKD stage 1 and 2 (CKD12). All patients were followed for 10 years to ascertain onset of ESRD.

Results

In Cox regression analysis, DLL1, DLL4, and JAG1 were strongly associated with progression to ESRD in T1D patients with CKD3 (P=1.6*10-10, p=5.1*10-8, and p=2.0*10-5, respectively) and in T2D patients with CKD3 (p=3.6*10-4, p=1.9*10-4, and p=6.1*10-4, respectively). Importantly, this significant association with ESRD for DLL1 and JAG1 were also found in T1D patients with CKD12 (p=2.8*10-6 and p=4.1*10-2), and DLL1 was the strongest predictor for ESRD in the combined panel, even after adjustment for relevant covariates (Hazard Ratio 1.48, p=8.4*10-6) (Table 1).

Conclusion

There were few previous reports about the association between circulating Notch signaling proteins and kidney diseases. Our finding is novel in that circulating ligands for Notch receptors, especially DLL1, are strongly associated with progression to future ESRD. Regulation of the specific circulating Notch ligands could become the new therapeutic targets to retard progression to ESRD in diabetes.

Table 1. Cox regression model for each group
 T1D CKD3
(n=219)
T2D CKD3
(n=144)
T1D CKD12
(n=190)
Combined
(n=553)
Adjusted
ProteinsHRP valueHRP valueHRP valueHRP value
DLL11.851.60E-101.853.60E-042.012.80E-061.488.40E-06
DLL41.675.10E-081.911.90E-041.123.80E-011.184.40E-02
JAG11.472.00E-051.786.10E-041.314.10E-021.055.30E-01
Notch11.093.10E-011.318.00E-021.143.20E-010.998.80E-01

Multivariate model was adjusted for baseline eGFR, HbA1c, ACR, and type of diabetes

Funding

  • Other NIH Support