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Kidney Week

Abstract: FR-PO097

Gene Deletion of the Na-Glucose Cotransporter SGLT2 Does Not Affect Kidney Injury or Recovery in a Murine Model of Severe AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Nespoux, Josselin, Department of Medicine, University of California, San Diego & VA San Diego Healthcare System, San Diego, California, United States
  • Patel, Rohit, Department of Medicine, University of California, San Diego & VA San Diego Healthcare System, San Diego, California, United States
  • Huang, Winnie, Department of Medicine, University of California, San Diego & VA San Diego Healthcare System, San Diego, California, United States
  • Freeman, Brent, Department of Medicine, University of California, San Diego & VA San Diego Healthcare System, San Diego, California, United States
  • Vallon, Volker, Department of Medicine, University of California, San Diego & VA San Diego Healthcare System, San Diego, California, United States
Background

In normoglycemia, the renal Na-glucose cotransporter SGLT2 reabsorbs ~97% of filtered glucose in the early proximal tubule, while SGLT1 reabsorbs the remaining glucose in the downstream S3 segment. Pretreatment with an SGLT2 inhibitor appeared protective at 24 hrs after ischemia-reperfusion (IR)-induced acute kidney injury (AKI) in mice (PLoS ONE 11(7):e0160478, 2016). Here we determined whether gene knockout of SGLT2 (KO) affects kidney injury or recovery following IR.

Methods

Male KO and wild-type (WT) mice (C57BL/6J) underwent sham surgery (Sham) or IR (25 min of bilateral renal artery clamping) under ketamine/xylazine anesthesia, while body temperature was maintained at 36-37°C (n=7-15/group). Urine and blood were collected at several time points. GFR was measured 14 days after IR by plasma elimination kinetics of FITC-sinistrin in conscious mice. Kidneys were harvested 23 days after IR for renal gene expression analysis by RT-qPCR.

Results

On day 1 after IR, plasma creatinine (by LC-MS-MS) increased to similar levels in KO-IR and WT-IR (1.96±0.19 vs 1.87±0.25 mg/dL, NS) vs Sham groups (0.14±0.01 vs 0.11±0.01 mg/dL, NS); fractional urinary glucose excretion (based on creatinine) increased from 27 to 62% in KO-IR and from 0.1 to 20% in WT-IR. IR reduced urine osmolality and increased plasma osmolality to a similar extent in KO-IR and WT-IR; this was associated with a similar increase in urinary KIM-1 to creatinine ratio, a marker of proximal tubule injury. On day 14, GFR was similarly reduced in KO-IR and WT-IR (2.4±0.2 vs 2.8±0.3 μL/min/g BW, NS) vs Sham groups (12.0±0.8 vs 11.9±0.9 μL/min/g BW, NS). On day 23, plasma creatinine (0.28±0.03 vs 0.32±0.03 mg/dL, NS) and plasma osmolality were partially restored in KO-IR and WT-IR, and urine osmolality and renal mRNA expression of Na-2Cl-K cotransporter NKCC2 were reduced at similar levels vs. Sham groups. Moreover, renal mRNA expression of markers of injury, fibrosis, inflammation and oxidative stress (KIM-1, type 1 collagen, TGFB1, MCP-1, NOX2) was significantly and similarly increased in KO-IR and WT-IR versus Sham groups.

Conclusion

Absence of SGLT2 did not affect the initial injury and impairment of kidney function or the subsequent partial kidney function recovery in a mouse model of IR-induced severe AKI.

Funding

  • NIDDK Support