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Abstract: PO0906

Podocyte-Specific Induction of KLF6 Attenuates Diabetic Kidney Disease in Mice

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Owusu Frimpong, Bismark, Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York, United States
  • Gujarati, Nehaben A., Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York, United States
  • Mallipattu, Sandeep K., Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York, United States
Background

Krüppel-Like Factor 6 (KLF6), a zinc finger transcription factor, is a key regulator of cytochrome c oxidase assembly in the podocytes. Podocyte-specific Klf6 knockdown increases the susceptibility to streptozotocin (STZ) induced-diabetic kidney disease (DKD). However, salutary effects of podocyte-specific KLF6 induction in DKD remain to be explored.

Methods

Podocyte-specific inducible human KLF6 (hKLF6) was generated in mice using the “Tet-on” system, by breeding NPHS2-rtTA mice with newly generated TRE-hKLF6 to generate hKLF6PODTA mice. TRE-KLF6 transgene were generated using the (TetO)7/CMV regulatory element driving the full-length human KLF6 coding sequence (CCDS 7060.1). Transgene was purified from plasmid vector sequences and microinjected into the pronucleus of FVB/N single-celled embryos. Founder mice were selected based on the level of hKLF6 induction after doxycycline (DOX) treatment. STZ + Unilateral nephrectomy (STZ-UNX) was utilized to induce DKD in mice. First, DOX diet was administered at 8 weeks of age in all mice. UNX or Sham was performed at 10 weeks of age followed by low-dose STZ or vehicle (VEH) treatment respectively, at 12 weeks for 5 consecutive days. DOX-STZ-UNX treated NPHS2-rtTA, DOX-VEH-Sham treated NPHS2-rtTA and hKLF6PODTA mice served as controls. All mice were euthanized at 20 weeks of age and assessed for functional and histological changes in the kidney.

Results

DOX-STZ-UNX treated hKLF6PODTA mice exhibited significantly lower albuminuria, focal and global glomerulosclerosis, mesangial expansion, and improved mice survival as compared to age and gender-matched DOX-STZ-UNX treated NPHS2-rtTA mice. DOX-STZ-UNX treated hKLF6PODTA mice also exhibited less tubulointerstitial fibrosis and inflammation (pathology scoring) as compared to age- and gender-matched DOX-STZ-UNX treated NPHS2-rtTA mice.

Conclusion

These data suggest that podocyte-specific induction of human KLF6 attenuates podocyte injury and DKD, and improves overall survival in mice.

Funding

  • NIDDK Support