Biomarker and drug-target discovery using proteomics in a new rat model of sepsis-induced acute renal failure

• Published in: Kidney international Vol. 70; no. 3; pp. 496 - 506
• Main Authors: Holly, M.K., Dear, J.W., Hu, X., Schechter, A.N., Gladwin, M.T., Hewitt, S.M., Yuen, P.S.T., Star, R.A.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-08-2006; Nature Publishing; Elsevier Limited
• Subjects: Acute Kidney Injury - etiology; Acute Kidney Injury - pathology; Acute Kidney Injury - urine; acute renal failure; Animals; Anti-Bacterial Agents - pharmacology; Bacterial diseases; Bacterial sepsis; Biological and medical sciences; Biomarkers - urine; Cecum; Cytokines - blood; DIGE; Disease Models, Animal; Drug Design; Electrophoresis - methods; Human bacterial diseases; Hydroxamic Acids - pharmacology; Infectious diseases; Kidney - pathology; Ligation; Liver - pathology; Male; Medical sciences; Metalloendopeptidases - urine; Mice; Mice, Inbred C57BL; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Nitrites - blood; proteomics; Proteomics - methods; rat model; Rats; Rats, Sprague-Dawley; Renal failure; sepsis; Sepsis - complications; Sepsis - drug therapy; Sepsis - urine; acute renal failure; rat model; DIGE; proteomics; sepsis; Animal model; Nephrology; Rat; Biological marker; Discoveries; Urology; Sepsis syndrome; Targeted drug; Kidney disease; Drug addiction; Urinary system disease; Acute; Rodentia; Biological indicator; Bacteremia; Infection; Vertebrata; Mammalia; Renal failure; Proteomics; Bacteriosis
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1038/sj.ki.5001575

Sepsis is one of the common causes of acute renal failure (ARF). The objective of this study was to identify new biomarkers and therapeutic targets. We present a new rat model of sepsis-induced ARF based on cecal ligation and puncture (CLP). We used this model to find urinary proteins which may be potential biomarkers and/or drug targets. Aged rats were treated with fluids and antibiotics after CLP. Urinary proteins from septic rats without ARF and urinary proteins from septic rats with ARF were compared by difference in-gel electrophoresis (DIGE). CLP surgery elevated interleukin (IL)-6 and IL-10 serum cytokines and blood nitrite compared with sham-operated rats. However, there was a range of serum creatinine values at 24 h (0.4–2.3 mg/dl) and only 24% developed ARF. Histology confirmed renal injury in these rats. Forty-nine percent of rats did not develop ARF. Rats without ARF also had less liver injury. The mortality rate at 24 h was 27% but was increased by housing the post-surgery rats in metabolic cages. Creatinine clearance and urine output 2–8 h after CLP was significantly reduced in rats which died within 24 h. Using DIGE we identified changes in a number of urinary proteins including albumin, brush-border enzymes (e.g., meprin-1-alpha) and serine protease inhibitors. The meprin-1-alpha inhibitor actinonin prevented ARF in aged mice. In summary, we describe a new rat model of sepsis-induced ARF which has a heterogeneous response similar to humans. This model allowed us to use DIGE to find changes in urinary proteins and this approach identified a potential biomarker and drug target – meprin-1-alpha.