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Abstract: FR-OR033

An APOL1-Induced FSGS Mouse Model That Mimics Human FSGS Nephropathy

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix


  • Rosenberg, Avi Z., Johns Hopkins University, Baltimore, Maryland, United States
  • Roshanravan, Hila, NIDDK, NIH, San Jose, California, United States
  • Delsante, Marco, Universita'' degli Studi di Parma, Baltimore, Maryland, United States
  • Hoek, Maarten, Third Rock Ventures, Redwood City, California, United States
  • Shin, Myung, Merck & Co., Inc, Kenilworth, New Jersey, United States
  • Kopp, Jeffrey B., NIDDK, NIH, San Jose, California, United States

In the present study, the we aimed to develop a CKD model in mice expressing apolipoprotein L1 (APO1) in order to generate a robust, reproducible model of APOL1 nephropathy. As reported, a bacterial artificial chromosome (BAC) that contains either the human APOL1 gene (BAC-APOL1 G0) or each of the renal risk variants (BAC-APOL1-G1 and -G2) were used to generate transgenic mice that constitutively expressed APOL1. At baseline, BAC-APOL1 G0, G1, and G2 mice had no renal phenotype despite genetic risk in the latter lines; therefore, we induced hypertension as second hit.


We used a combination of Saline drinking water, Angiotensin II infusion, uniNephrectomy and Deoxycorticosterone acetate pellets (SAND model)


After 3 weeks, mice developed albuminuria (G0, 2205 ± 84 mg/g, G1, 3840 ± 363 mg/g, G2 3447 ± 111 mg/g, and wild type, 2085 ± 202 mg/g) and uremia, with elevated blood urea nitrogen (BUN). SAND intervention in G1 and G2 mice led to reduced cortical thickness and podocyte number compared to G0 mice. SAND G1 and G2 mouse kidneys showed focal global and segmental glomerulosclerosis (FSGS), as well as glomerular lipid accumulation by oil red O staining. Differentially expressed genes in kidney cortex were identified based on log2 fold change and false discovery rate (FDR) of <0.05. In SAND G1 mice Aoc1, C1q, Ncam1, Scamp1, and Tbca were downregulated and Hmgcs2 was upregulated compared to G0 mice. We examined expression of 60 FSGS-related genes, 64 cytokines, 63 cytokine receptors,52 chemokines and 33 chemokine receptors in order to identify additional differentially-expressed genes in G1 and G2 mice, using a cutoff of log2 fold change of <0.05. Ccrl2 was shown to be upregulated in G1 and G2 transgenic mice compared to WT and APOL1-G0 mice


In summary, we have shown that with the SAND model of hypertensive nephropathy, BAC-APOL1 G1 and G2 mice manifest more severe proteinuria, FSGS, and distinct patterns of gene expression.


  • NIDDK Support