Kidney Week

Abstract: SA-PO103

A Novel Surgery-Induced Rat Model of Diabetic Nephropathy Displaying Progressive Albuminuria, Glomerular Hypertrophy, and Glomerulosclerosis

Session Information

• Diabetic Kidney Disease: Basic - III
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Østergaard, Mette Viberg, Gubra ApS, Hørsholm, Denmark

Mette Viberg Østergaard,

• Johansen, Thea Thougaard, Gubra ApS, Hørsholm, Denmark

Thea Thougaard Johansen,

• Secher, Thomas, Gubra ApS, Hørsholm, Denmark

Thomas Secher,

• Sembach, Frederikke Emilie, Gubra ApS, Hørsholm, Denmark

Frederikke Emilie Sembach,

• Rigbolt, Kristoffer, Gubra ApS, Hørsholm, Denmark

Kristoffer Rigbolt,

• Skarsfeldt, Torben, Serodus, Oslo, Norway

Torben Skarsfeldt,

• Vrang, Niels, Gubra ApS, Hørsholm, Denmark

Niels Vrang,

• Fosgerau, Keld, Gubra ApS, Hørsholm, Denmark

Keld Fosgerau,

• Fink, Lisbeth N., Gubra ApS, Hørsholm, Denmark

Lisbeth N. Fink,

Background

Diabetic nephropathy (DN) is a long-term complication of diabetes characterized by albuminuria and loss of kidney function. No new therapies targeting DN have been introduced for decades, partly due to the lack of preclinical animal models recapitulating key features of human DN. Here, we characterized a novel preclinical model of DN in pancreatectomized (Px) uni-nephrectomized (UNx) rats.

Methods

Px-UNx (n=11) and sham (n=12) operations were performed at 8 wks of age in male SPD rats. Blood glucose was >18 mmol/L in Px-UNx rats from 2 wks post-surgery. Urinary renal injury markers were measured 2, 6 and 9 wks after surgery and glomerular filtration rate (GFR) 9 wks after surgery. At termination 11 wks post-surgery, kidneys were processed for histology, stereology and next generation sequencing (NGS).

Results

Urinary albumin and NGAL excretion was increased from 2 wks post-surgery in Px-UNx vs Sham and highest after 9 wks for both albumin (13473±7619 vs 370±170 µg/mg creatinine, p<0.001) and NGAL (13.28±1.76 vs 2.68±0.43 µg/mg creatinine, p<0.001). Urinary podocalyxin excretion was increased from 6 wks and peaked 9 wks post-surgery in Px-UNx (195.2±41.9 vs 11.8±2.0 ng/mg creatinine, p<0.001). GFR was higher in Px-UNx vs Sham (8.2±0.3 vs 6.6±0.3 mL/min/kg, p<0.01). At termination, plasma urea was increased in Px-UNx (9.4±0.7 vs 5.5±0.2 mmol/L, p<0.001). Right kidney weight and volume was nearly doubled in Px-UNx vs Sham (both p<0.001), as were renal cortex (69.1% increase, p<0.001) and glomerulus volumes (57.7% increase, p<0.001). Kidney fibrosis (398±24 vs 210±9.8 mg collagen III, p<0.001) and glomerulosclerosis (11.1±0.8 vs 6.3±0.3 mm³ collagen IV, p<0.001) was increased in Px-UNx vs Sham rats. Px-UNx increased gene expression of tubular injury markers (KIM-1, NGAL), collagens and fibronectin in renal cortex and reduced nephrin expression.

Conclusion

The Px-UNx model of DN develops extensive renal hypertrophy, hyperfiltration and fibrosis concomitant with early excretion of both glomerular and tubular injury markers. In rats, Px in combination with UNx represents a novel time-saving and robust alternative to STZ-induced diabetes and genetic models for preclinical drug development targeting DN.