Abstract: PO1998
Pharmacologic Blockade of the Natriuretic Peptide Clearance Receptor Ameliorates Glomerular Disease in an Animal Model of FSGS
Session Information
- Podocyte Biology
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1204 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
Glomerular podocytes play a key role in glomerular disease processes. Accumulating evidence suggests that cGMP signaling has podocyte protective effects in kidney diseases (J Am Soc Nephrol 28: 260, 2017). cGMP is produced by nitric oxide and by natriuretic peptides (NPs). NPs are the predominant source of cGMP generation in podocytes. NPs stimulate cGMP production by binding to NP receptors (NPRs). NPRA and NPRB stimulate cGMP generation. In contrast, NPRC binds and degrades NPs. Podocytes express all three NPRs (NPRA, NPRB, and NPRC). We hypothesized that blockade of NPRC would enhance local NP levels, promote cGMP signaling in podocytes and attenuate glomerular injury.
Methods
We blocked clearance of NPs by NPRC using the pharmacologic agent ANP (4-23), which specifically binds NPRC without binding NPRA or NPRB. For the experiments, we used a mouse transgenic (TG) model of focal segmental glomerulosclerosis (FSGS) created in our laboratory (J Clin Invest 125:1913, 2015). These TG mice express a constitutively active Gq α-subunit specifically in podocytes. In these animals, treatment with a single dose of the podocyte toxin puromycin aminonucleoside (PAN) causes robust albuminuria in TG mice, but only mild disease in non-TG animals.
Results
PAN induced heavy proteinuria in vehicle-treated TG mice at day 14 (1426 ± 425 [day 14] vs. 49 ± 19 [baseline] ug/mg creatinine; P = 0.0002). The increase in albuminuria at day 14 was significantly reduced by treatment with ANP(4-23) (1426 ± 425 [vehicle] vs. 383 ± 157 [ANP(4-23)] ug/mg creatinine; P = 0.003). Treatment with ANP(4-23) also tended to reduce the number of mice with glomerular injury (83% [vehicle] vs 54% [ANP(4-23)]; P = NS). Systolic BP was similar in mice receiving ANP(4-23) and in the vehicle treated group (129 ± 3 [vehicle] vs. 127 ± 3 [ANP(4-23)] mm Hg; P = NS). Urinary cGMP excretion tended to be higher in ANP(4-23) treated mice (6.7 ± 1.0 ng/mg creatinine) compared to mice treated with vehicle (4.9 ± 1.0 ng/mg creatinine), but this difference was not statistically significant.
Conclusion
These data suggest that: 1. Pharmacologic blockade NPRC may be a useful strategy for treating proteinuric kidney diseases, and 2. Treatment outcomes might be improved by optimizing blockade of the NPRC to more effectively inhibit clearance of NPs from the circulation.
Funding
- Veterans Affairs Support