Effect of Lisinopril on Glomerular and Tubular Injury in a Surgical Rat Model of Progressive CKD and Kidney Failure

Background: Development of renal fibrosis is a hallmark of chronic kidney disease (CKD), underlying the progressive loss of kidney function and progression to end-stage kidney disease. The 5/6 nephrectomy (Nx) rat model of CKD displays progressive albuminuria, glomerulosclerosis, tubulointerstitial fibrosis, and loss of kidney function. Here, we characterised the effect of lisinopril, a standard ACE inhibitor, on kidney histopathology, renal biochemical markers, and kidney function in 5/6 Nx rats. Methods: Male Wistar rats (9 weeks old) underwent either sham operation or 2/3 nephrectomy of the right kidney at week -4 and full nephrectomy of left kidney at week -2. Rats were randomised into study groups at week -1 based on plasma urea, creatinine, and body weight. Sham rats received vehicle and 5/6 Nx rats received either vehicle or Lisinopril (20 mg/kg, PO, QD), for a total of 8 weeks, starting on day 1. Urine was sampled for analysis of albumin-to-creatinine ratio (ACR) (week 7) and the glomerular filtration rate (GFR) (week 8). Terminal plasma was sampled for analysis of urea albumin and creatinine. The remaining right kidney was harvested for quantitative histological assessment of glomerulosclerosis (PAS staining), macrophage infiltration (CD68), tubular injury (KIM-1), and fibrosis (Col1a1). Results: The 5/6 Nx rat model displayed significant increase of renal biomarkers, GFR decline, glomerulosclerosis, tubular injury, renal macrophage infiltration and fibrosis as compared to sham-operated rats. Treatment with lisinopril significantly reduced albumin-to-creatinine ratio and significantly reduced tubular injury. The 5/6 Nx rat model is applicable for probing preclinical drug candidate for CKD. Conclusion: 5/6 Nx rats displayed loss of kidney function including declined GFR and increased albuminuria as well as key histopathological features of chronic kidney disease. Treatment with Lisinopril significantly reduced ACR and tubular injury. Funding: Commercial Support - Gubra