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Kidney Week

Abstract: PO0378

Kidney-Specific Intestinal Alkaline Phosphatase (IAP) in Transgenic Mice Protects Lipopolysaccharide (LPS)-Induced Inflammation and Renal Failure

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Ghosh, Siddhartha S., Virginia Commonwealth University Medical Center, Richmond, Virginia, United States
  • Gipson, Graham Thomas, Virginia Commonwealth University Medical Center, Richmond, Virginia, United States
  • Kang, Joshua Minsoo, Virginia Commonwealth University Medical Center, Richmond, Virginia, United States
  • Ghosh, Shobha, Virginia Commonwealth University Medical Center, Richmond, Virginia, United States
  • Gehr, Todd W., Virginia Commonwealth University Medical Center, Richmond, Virginia, United States
Background

LPS is a major player in septic AKI. However, LPS can be dephosphorylated to an inactive form by IAP. We generated kidney specific IAP transgenic mice (Tg) mice to test whether the targeted increase in IAP can decrease inflammation and improve renal function.

Methods

Tg mice were developed in C57Bl6 background using human chimeric IAP under the control of villin promoter making them kidney specific albeit some expression was also observed in the intestine. The 3’ prime end of the transgenic codon had a cmyc tag to distinguish human IAP from resident mouse IAP. Tg and non-transgenic littermates (Wild type, WT) were given 10 mg/kg LPS. Wild type control (Con) received saline. Renal function tests, plasma BUN creatinine, proteinuria, and albuminuria were performed. Plasma, Kidney, and liver were harvested after 12 hours for western blots and ELISA. Electron microscopy (EM) was done to evaluate podocytes.

Results

Serum creatinine and BUN were 2.5 and 3 fold higher in WT compared to Con (p<0.01), the increases were attenuated in Tg (p<0.05). In WT proteinuria and albuminuria were 3 and 5 fold higher than Con (p<0.05) these were attenuated in Tg (p<0.05). Cytokines (IL-1β, IL-6, and TNFα) in the liver, kidney, and plasma of WT after LPS injection was 2 to 4-fold higher than Con. However, in the liver of Tg+LPS, only TNFα was significantly reduced. Plasma and kidney cytokines of Tg+LPS were significantly lower than WT+LPS (Fig). The reduction of cytokines in the kidney of Tg+LPS was more profound than the plasma of TG+LPS. Podocyte effacement in Tg mice was less severe than WT. We could detect cmyc in plasma and kidney in Tg mice.

Conclusion

This study shows targeted increase of IAP in the kidney can abate LPS mediated deterioration of renal function, inflammation, and podocyte effacement. IAP has been shown to be released after LPS administration perhaps as a protective mechanism. An increase in plasma cmyc after LPS injection indicate that human IAP could have been secreted in the blood from the kidney or intestine. This may have decreased the inflammatory burden in the plasma.

Fold changes in cytokines