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Abstract: FR-OR98

Podocyte-Specific Knockout (KO) of the Natriuretic Peptide Clearance Receptor (NPRC) Ameliorates Glomerular Injury in a Mouse Model of Focal Segmental Glomerulosclerosis (FSGS)

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Wang, Liming, Duke University, Durham, North Carolina, United States
  • Tang, Yuping, Duke University, Durham, North Carolina, United States
  • Buckley, Anne, Duke University, Durham, North Carolina, United States
  • Spurney, Robert F., Duke University, Durham, North Carolina, United States
Background

Natriuretic peptides (NPs) have podocyte protective effects by stimulating cGMP generation (J Am Soc Nephrol 28: 260, 2017). NPs stimulate cGMP production by binding to NP receptors (NPRs). Atrial NP (ANP) and the C-type NP (CNP) stimulate cGMP generation by binding to NPRA and NPRB, respectively. In contrast, the NP clearance receptor (NPRC) binds and degrades NPs and, in turn, negatively regulates the beneficial effects of NPs. Podocytes express all three NPRs (NPRA, NPRB, and NPRC). We previously found that pharmacologic blockade of NPRC reduced proteinuria in a mouse model of FSGS (Physiological Reports. 2021;9:e15095). In this study, we investigated the effects of podocyte specific KO of NPRC in FSGS using the same mouse model.

Methods

NPRC was deleted specifically in podocytes in a transgenic (TG) mouse model of FSGS created in our laboratory (J Clin Invest 125:1913, 2015). These TG mice express a constitutively active Gq α-subunit specifically in podocytes (Gq mice). In these animals (Gq mice), treatment with a single dose of the podocyte toxin puromycin aminonucleoside (PAN) causes robust albuminuria, but only mild disease in wild type (WT) mice.

Results

Podocyte specific KO of NPRC significantly reduced albuminuria in Gq mice 10 days after PAN injection (6094 ± 1130 [NPRC+/+] vs. 2740 ± 627 [NPRC-/-] ug/mg creatinine; P = 0.007). KO of NPRC also significantly reduced the number of Gq mice with glomerular sclerosis (GS) (85% [NPRC+/+; N = 20] vs 46% [NPRC-/-; N = 13]; P = 0.026). Consistent with the GS results, there was a significant increase in mRNA and protein levels of the myofibroblast marker alpha-smooth muscle actin (alpha-SMA) in NPRC+/+ Gq mice, and this increase in alpha-SMA expression was significantly reduced in NPRC-/- Gq mice. Treatment with PAN also decreased expression of both nephrin and podocin in NPRC+/+ Gq mice, which was prevented by podocyte specific KO of NPRC.

Conclusion

Podocyte specific KO of NPRC significantly decreased albuminuria, reduced GS, decreased myofibroblast activation and preserved expression of the podocyte proteins nephrin and podocin in a mouse model of FSGS. These data suggest that strategies to augment the effects of NPs might be a useful therapeutic approach for treating FSGS.

Funding

  • Other NIH Support