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Kidney Week

Abstract: TH-PO088

Diabetes and Obesity Increase the Severity of Ischemia-Reperfusion Induced AKI in ZSF1 Rats

Session Information

  • AKI: Mechanisms - I
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Ma, Li-Jun, Cardiovascular, Metabolism, and Retina at The Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, Pennsylvania, United States
  • Du, Fuyong, Cardiovascular, Metabolism, and Retina at The Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, Pennsylvania, United States
  • Albarazanji, Kamal, Cardiovascular, Metabolism, and Retina at The Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, Pennsylvania, United States
  • Liu, Jianying, Cardiovascular, Metabolism, and Retina at The Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, Pennsylvania, United States
  • Li, Qiu, Cardiovascular, Metabolism, and Retina at The Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, Pennsylvania, United States
  • Guo, Lili, Cardiovascular, Metabolism, and Retina at The Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, Pennsylvania, United States
  • Qi, Jenson, Cardiovascular, Metabolism, and Retina at The Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, Pennsylvania, United States
  • Ho, George, Cardiovascular, Metabolism, and Retina at The Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, Pennsylvania, United States
  • Meng, Rong, Cardiovascular, Metabolism, and Retina at The Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, Pennsylvania, United States
  • Chen, Tao, Preclinical Sciences and Translational Safety at Janssen, Johnson & Johnson, Spring House, Pennsylvania, United States
  • Camacho, Raul, Cardiovascular, Metabolism, and Retina at The Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, Pennsylvania, United States
  • Nawrocki, Andrea R., Cardiovascular, Metabolism, and Retina at The Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, Pennsylvania, United States
Background

Acute kidney injury (AKI) is a multifactorial disease with various etiologies including cardiac surgery and sepsis. Preclinical AKI is typically induced in young and healthy rodents and the predictive value of preclinical AKI models for drug discovery is unclear. Obese, diabetic ZSF1 rats display multiple preexisting metabolic complications including kidney dysfunction. We show that obese, diabetic ZSF1 rats are more susceptible to ischemia reperfusion injury (IRI) induced-renal function decline and tubular injury compared to lean, non-diabetic ZSF1 rats.

Methods

AKI was induced in male, obese, diabetic ZSF1 (CRL) or age-matched, lean ZSF1 rats at age of 17-18 weeks by unilateral IRI with uninephrectomy (Unx) and followed for 1 or 7 days. Renal function was assessed by transcutaneous glomerular filtration rate (tGFR, FITC-labeled sinistrin, Medibeacon) and plasma creatinine (LC/MS). Urinary Nephrocheck, gene expression and kidney histology were assessed.

Results

24 hrs post IRI surgery, glomerular filtration rate (tGFR) was dramatically decreased in both obese ZSF1 Unx/IRI and lean ZSF1 Unx/IRI groups compared to controls. Further, IRI in obese ZSF1 rats caused significantly greater renal function decline indicated by plasma creatinine, and more severe tubular necrosis. Tubular injury marker genes (Kim1, NGAL) were upregulated in kidney, while mitochondrial genes (mdufa2, uqcrs1, ATP5g1, PPARgc1) and tubular integrity marker genes (AQP1, rGT1) were downregulated to a greater extent in obese vs lean ZSF1 IRI kidneys. Urinary Nephrocheck levels were higher in obese vs lean ZSF1 rat IRI. The decline in kidney function persisted in obese ZSF1 IRI rats but recovered in lean ZSF1 IRI rats from day 3 to 7. Overall, we observed 25% mortality in obese ZSF1 rats with Unx/IRI while the moderate AKI was reversed in lean rats after IRI surgery without progression to kidney failure.

Conclusion

Our data indicate that obese and diabetic ZSF1 rats with underlying metabolic disease and albuminuria exhibit severe renal function decline after a single, moderate ischemic episode relative to non-diabetic, lean counterparts. Our data suggest that typically used rodent IRI models for AKI do not represent the full spectrum of the human disease.

Funding

  • Commercial Support