Promoting Podocyte Protective Natriuretic Peptide Signaling in Proteinuric Kidney Diseases
Abstract
Glomerular podocytes play a key role in glomerular disease processes. Accumulating evidence suggests that cGMP signaling has podocyte protective effects in kidney diseases. Production of cGMP is stimulated 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, in turn, attenuate podocyte and glomerular injury. To examine this hypothesis, we blocked clearance of NPs by NPRC using the pharmacologic agent ANP (4-23), which specifically binds NPRC without binding NPRA or NPRB. We then examined the effect of inhibiting NP clearance in a mouse model of focal segmental glomerulosclerosis (FSGS) created in our laboratory. We found that treatment with ANP(4-23) significantly reduced albuminuria (1426+- 425 [vehicle] vs. 383+-157 [ANP(4-23)] ug/mg creatinine; P = 0.003), preserved expression of the podocyte marker nephrin and tended to reduce the number of mice with glomerular injury (83 percent [vehicle] vs 54 percent [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. 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2020
- Accession Number
- AD1108784
Entities
People
- Robert F Spurney
Organizations
- Duke University