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Kidney Week

Abstract: FR-PO367

SerpinA3K Deficiency Ameliorates Diabetic Kidney Disease (DKD)

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • González Soria, Isaac, Universidad Nacional Autonoma de Mexico, Ciudad de México, Ciudad de México, Mexico
  • Soto Valadez, Axel Daniel, Universidad Nacional Autonoma de Mexico, Ciudad de México, Ciudad de México, Mexico
  • Martinez-Rojas, Miguel Angel, Universidad Nacional Autonoma de Mexico, Ciudad de México, Ciudad de México, Mexico
  • Palacios-Brito, Esmeralda, Universidad Nacional Autonoma de Mexico, Ciudad de México, Ciudad de México, Mexico
  • Pérez-Villalva, Rosalba, Universidad Nacional Autonoma de Mexico, Ciudad de México, Ciudad de México, Mexico
  • Diaz-Villaseñor, Andrea, Universidad Nacional Autonoma de Mexico, Ciudad de México, Ciudad de México, Mexico
  • Bobadilla, Norma, Universidad Nacional Autonoma de Mexico, Ciudad de México, Ciudad de México, Mexico
Background

We showed that SerpinA3K is an early urinary biomarker of Acute Kidney Injury (AKI) to Chronic Kidney Disease (CKD) transition. SerpinA3K or anti-chymotrypsin is a serine protease inhibitor with non-canonical functions such as: antioxidant, anti-inflammatory, and anti-fibrotic in rodent diabetic retinopathy. Nevertheless, we recently showed that AKI is attenuated in SerpinA3K deficient mice by inducing higher expression of antioxidant defense, however, its involvement in CKD remains elusive. This study was designed to evaluate the impact of SerpinA3K absence in DKD.

Methods

Thirty wildtype (WT) [SerpinA3K+/+] and thirty knock-out (KO) [SerpinA3K-/-] male mice after breastfeeding were randomized in the following six groups: Standard Diet (WT+SD and KO+SD), High Fat Diet (WT+HFD and HFD+KO), and Streptozotocin (STZ) [100 mg/kg] + HFD (WT+DKD and KO+DKD). Glucose monitoring was done every 15 days. A cut-off point was established above 500 mg/dL to receive insulin 2 days per week to increase animal survival. Urine collection was done monthly. After 7 months of follow-up, each group was euthanized for kidney functional, histological, and molecular analyses. Differences between groups were analyzed through ANOVA and post-hoc testing with a significance level of p<0.05.

Results

HFD feeding induced obesity, hypercholesterolemia, hyperleptinemia, and hyperinsulinemia, without any differences between genotypes, but increased serum IL6 in the WT+HFD was not evident in the KO+HFD group. In addition, the WT+DKD group exhibited hyperglycemia above 500 mg/dL, since, 15 days after STZ requiring insulin, and exhibited insulin resistance (HOMA-IR). Interestingly, these effects were not seen in the KO+DKD group, in which, glycemia was below 400 mg/dL and non-insulin requirement. GFR measured by fluorescein sinistrin was significantly increased in the WT+DKD but not in the KO+DKD group. Furthermore, the WT+DKD group exhibited an increase in Hif1a, Il6, and Tgfb1 which was not seen in the KO+DKD.

Conclusion

The absence of SerpinA3K was associated with DKD attenuation. This protective effect seems to be mediated by improving metabolic health against hyperglycemia. Nevertheless, the mechanisms and causes of this protection required further studies to deep into the role of SerpinA3K in DKD induced by STZ.

Funding

  • Government Support – Non-U.S.