Anti-KITLG Therapy in Renal Injury
November 09, 2019 | 10:00 AM - 12:00 PM
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Anti-KITLG Therapy in Renal Injury
Glomerular Diseases: Fibrosis, Extracellular Matrix
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix
- Walter, Debra L., University of Michigan, Milan, Michigan, United States
- Zhang, Hongyu, University of Michigan, Milan, Michigan, United States
- Chu, Cindy, University of Michigan, Milan, Michigan, United States
- O'Connor, Christopher Lund, University of Michigan, Milan, Michigan, United States
- Killen, Paul D., University of Michigan, Milan, Michigan, United States
- Phillips, Martin D., Opsidio LLC, Bryn Mawr, Pennsylvania, United States
- Ju, Wenjun, University of Michigan, Milan, Michigan, United States
- Lukacs, Nicholas W., University of Michigan, Milan, Michigan, United States
- Bitzer, Markus, University of Michigan, Milan, Michigan, United States
Debra L. Walter,
Christopher Lund O'Connor,
Paul D. Killen,
Martin D. Phillips,
Nicholas W. Lukacs,
Activation of TGFB signaling promotes organ fibrosis. KIT/KITLG signaling regulates inflammation and fibrosis in humans and animal models and cross-talks with TGFB signaling, but its role in mediating kidney fibrosis remains unclear. Isoform-specific anti-KITLG-antibody therapy is in preclinical development. Therefore, we examined the effect of KITLG inhibition on glomerulosclerosis and interstitial fibrosis in ALB-TGFB1 transgenic mice (TGFB1-TG).
Ten-day old TGFB1-TG mice were treated biweekly with a monoclonal antibody against KITLG (aKITLG) (n=17) or control-IgG (IgG) (n=15) and euthanized after two weeks. Six wild-type mice were used as non-diseased controls. Pathologic phenotype was assessed blindly by an experienced nephropathologist using trichrome stained sections. RNA-sequencing was performed on HiSeq4000 and analyzed using dseq2 and limma-voom, and further assessed using Ingenuity pathway analysis (IPA). IgG and aKITLG-treated mice were separated into mild (n=6) and severe (n=9-10) groups using previously published parameters (PMID 19465643) and principal component analysis of gene expression profiles. Podocyte density, mesangial index and glomerulosclerosis were quantitated morphometrically and plasma KITLG (pKITLG) levels measured by ELISA.
Severe IgG mice had significantly higher pKITLG and mesangial index and lower podocyte density compared to mild IgG mice (p<0.01). pKITLG levels significantly correlated to podocyte density (inversely) and mesangial index (positively) (p<0.05). aKITLG mice had no change in body weight and trended towards improved survival. aKITLG mice demonstrated significantly reduced fibrosis and mesangial index (p<0.05) and a trend towards improved podocyte density compared with IgG mice. Expression of extracellular matrix genes Col1a1, Col3a1 and Col6a3 was significantly reduced in kidney cortex of aKITLG vs IgG mice (p<0.05). IPA identified several candidate signaling pathways altered by aKITLG.
Our findings that pKITLG increased with severity and aKITLG antibody ameliorated kidney damage in TGFB1-TG mice support aKITLG therapy as a candidate intervention for fibrotic kidney disease. Studies examining human biofluids and aKITLG therapy in other mouse models of kidney injury are ongoing.
- NIDDK Support