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Abstract: PO0701

Polyamine Catabolism Is Enhanced in Streptozotocin-Treated Mice and in Cultured Proximal Tubule Cells Exposed to High Glucose Levels: A Possible Role in Tubular Injury in Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Zahedi, Kamyar A., University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
  • Barone, Sharon L., University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
  • Brooks, Marybeth, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
  • Soleimani, Manoocher, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
Background

Polyamines are indispensable to cell growth and survival. Their cellular levels are regulated via import, export and metabolism. Their catabolism is mediated via the activities of spermine oxidase (SMOX) and spermine spermidine-N1-acetyltransferase (SAT1)/Acetylpolyamine oxidase (PAOX) cascade. Enhanced polyamine catabolism mediates cellular injury by induction of DNA and mitochondrial damage, activation of the endoplasmic reticulum stress/unfolded protein response (ERS/UPR) pathway, and innate immunity. Studies indicate that mitochondrial dysfunction, innate immune response and ERS/UPR are important mediators of tubular injury in diabetic nephropathy. We posit that polyamine catabolism is activated in diabetes mellitus and plays an important role in tubular injury.

Methods

The expression of polyamine catabolic enzymes was examined in streptozotocin (STZ)-induced diabetes in mice and HK-2 proximal tubule cells exposed to high glucose (30mM) levels. The expression levels of SAT1 and SMOX were determined by northern and western blot analyses. Nephron segment expression and localization of SAT1 and SMOX in STZ-treated mice was determined by immunohistochemistry and immunofluorescence microscopy.

Results

Expression of SAT1 and SMOX were elevated in the kidneys of STZ-treated mice compared to their vehicle-treated counterparts. Immunohistochemical and immunofluorescence microscopic studies revealed that SAT1 and SMOX expression are increased the proximal tubule, distal convoluted tubule and collecting duct epithelial cells. In vitro studies using HK-2 cells demonstrated that the expression of both SAT1 and SMOX increases in response to exposure to 30mM glucose.

Conclusion

Expression of polyamine catabolic enzymes, SAT1 and SMOX, is increased in proximal tubules, distal convoluted tubules and collecting ducts of mice with diabetes mellitus. Similarly, exposure of HK-2 cells to 30mM glucose increased the expression of both SAT1 and SMOX transcripts. Based on these studies and their known injurious effects, we propose that SAT1 and SMOX play a significant role in the mediation of renal injury in diabetes mellitus likely through the induction of oxidative injury, mitochondrial damage, elevated ERS/UPR and activation of innate immune response.

Funding

  • Veterans Affairs Support