Abstract: SA-PO331

Renal Release of Ac-SDKP Is Part of an Antifibrotic Peptidergic System in the Kidney

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Romero, Cesar A., Henry Ford Hospital, Detroit, Michigan, United States
  • Kumar, Nitin, Henry Ford Health System, Detroit, Michigan, United States
  • Carretero, Oscar A., Henry Ford Hospital, Detroit, Michigan, United States
Background

Ac-SDKP is a natural peptide with anti-fibrotic and anti-inflammatory properties in vascular, myocardial and kidney diseases. Ac-SDKP is present in urine and increases under angiotensin converting enzyme inhibitors (ACEi). Ac-SDKP is released from Thymosin B4 (Tβ4) by two step enzymatic reactions by meprin-α and the prolyl oligopeptidase enzymes (POP) and degraded by angiotensin converting enzyme (ACE). Tβ4, Meprin-α and POP enzymes has been reported in kidney. We hypothesized that Ac-SDKP is produced in the kidney.

Methods

We evaluated the presence of Tβ4, Meprin-α and POP mRNA by analyzing the trascriptome in each segment of the nephron using the public access NHI database ESBL. We confirmed kidney expression of Meprin-α and POP by immunofluorescence and enzyme activity measurements. The Stop Flow Pressure technique was used to evaluate the Ac-SDKP formation in different segments of the nephron, in normal condition, under POP inhibition (POPi) and ACEi. All experiments were performed in Sprague-Dawley rats.

Results

Tβ4 mRNA was present in all the nephron segments, however Meprin-α mRNA was only expressed in proximal tubule (s3 region), and POP mRNA was present in proximal tubule, loop of Henle (inner medulla) and distal nephron (distal, connecting and collecting tubules). We confirmed the expression of Meprin-α by immunofluorescence in proximal tubules and the POP was found in the distal convoluted tubule in cortex and in higher amounts in the medullary region. POP activity was also high in kidney medulla (Cortex 613.8±352.1 vs. Medulla 1162.2±408.5 pmol/min/mg prot; P<0.01). The Stop flow technique showed the high Ac-SDKP/Inulin ratio in the distal nephron: 10.5±0.8 vs. 4.2±0.1 in the proximal segments (p<0.01). POPi infusion into the kidney decreased Ac-SDKP/Inulin in comparison to the vehicle group in distal (10.5±0.8 vs 5.6±0.8, p<0.01) and proximal nephron segments (4.22±0.1 vs. 2.1±0.2, p<0.01). ACEi increased the Ac-SDKP content in all nephron segments, mainly in the distal part. Chronic infusion of POP inhibitor increase kidney medullary interstitial fibrosis and that was prevented by Ac-SDKP (Fibrotic area in %: Vehicle 1.84±0.8, POPi 3.3±1*, POPi+Ac-SDKP 1.37±0.58; *p<0.001POPi vs. Vehicle and POPi+Ac-SDKP).

Conclusion

We conclude that Ac-SDKP is released by the nephron and has an important antifibrotic effect in the kidney.

Funding

  • Other NIH Support