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Abstract: PO1691

Regression of Severe Preexisting Glomerular Pathology in a Mouse FSGS Model in Response to Treatment with Macula Densa-Derived Biologicals

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Gyarmati, Georgina, University of Southern California Keck School of Medicine, Los Angeles, California, United States
  • Shroff, Urvi Nikhil, University of Southern California Keck School of Medicine, Los Angeles, California, United States
  • Izuhara, Audrey, University of Southern California Keck School of Medicine, Los Angeles, California, United States
  • Peti-Peterdi, Janos, University of Southern California Keck School of Medicine, Los Angeles, California, United States
Background

Macula densa (MD) cells localized at the glomerular vascular pole synthesize and release numerous vasoactive autocoids and newly identified angiogenic (e.g. CCN1) and glomerulotrophic factors that act in a paracrine fashion to maintain high renal/glomerular blood flow and endogenous tissue remodeling. The present study aimed to test the tissue regenerative therapeutic potential of MD-derived biologicals in vivo in a mouse model of focal segmental glomerulosclerosis (FSGS).

Methods

BalbC mice with Adriamycin-induced stable, severe FSGS and albuminuria (albumin/creatinine ratio ACR>10,000mg/g) were randomized into 5 groups and started daily ip injections (150ul each) of either saline (S), human recombinant (hr)CCN1 in low-dose (0.3 ng/mouse) (L), hrCCN1 high-dose (2 ug/mouse) (H), DMEM/F12 control (D), and conditioned culture media of the new MD cell line mMDGeo (MD) for 4 weeks. Transcutaneous GFR (MediBeacon) and ACR were measured weekly. Terminal histological analysis was performed using PAS and Trichrome staining.

Results

Kidney injury was severe at the onset (GFR 1160±51 μL/min/100 g BW, ACR 11219±637) and was sustained throughout the 4 weeks of treatment in control S and D groups (GFR: 1080±143, 992±164; ACR: 10227±5869, 3958±1638, respectively). In contrast, a progressive and significant improvement in kidney function was observed in response to both L, H, and MD treatment (ACR reduced to 1342±573, 921±270, 1113±151, respectively; GFR increased to 1453±100 μL/min/100 g BW in MD group). Similarly, p57+ podocyte number per glomerular area (11±0.4 in L, 12±0.6 in H vs 3.9±0.43 in S;14±0.6 in MD vs 5.5±0.9 in D), GS index (131±2.4 in L, 130±2.3 in H vs 173±3.4 in S; 113±1.9 in MD vs 152±3 in D based on PAS staining) and tissue fibrosis index (67±2 in L, 57±2 in H vs 83±3 in S; 47±2 in MD vs 80±3 in D based on Picrosirius staining density) improved significantly in response to treatment with MD biologicals.

Conclusion

This in vivo preclinical study confirmed that the supplementation of key MD cell-derived factors in the form of injectable biologicals can augment endogenous kidney tissue repair and restores kidney function in a mouse model of FSGS. Targeting MD cell mechanisms is a new potent tissue regenerative therapeutic strategy for kidney diseases.

Funding

  • NIDDK Support