Glomerular podocytes play a key role in proteinuric diseases. Accumulating evidence suggests that cGMP signaling has podocyte protective effects. The major source of cGMP generation in podocytes is
natriuretic peptides. The
natriuretic peptide clearance receptor (NPRC) binds and degrades
natriuretic peptides. As a result, NPRC inhibits
natriuretic peptide-induced cGMP generation. To enhance cGMP generation in podocytes, we blocked
natriuretic peptide clearance using the specific NPRC
ligand ANP(4-23). We then studied the effects of NPRC blockade in both cultured podocytes and in a mouse transgenic (TG) model of
focal segmental glomerulosclerosis (FSGS) created in our laboratory. In this model, a single dose of the podocyte toxin
puromycin aminonucleoside (PAN) causes robust
albuminuria in TG mice, but only mild disease in non-TG animals. We found that
natriuretic peptides protected cultured podocytes from PAN-induced apoptosis, and that ANP(4-23) enhanced
natriuretic peptide-induced cGMP generation in vivo. PAN-induced heavy
proteinuria in vehicle-treated TG mice, and this increase in
albuminuria was reduced by treatment with ANP(4-23). Treatment with ANP(4-23) also reduced the number of mice with glomerular injury and enhanced urinary cGMP excretion, but these differences were not statistically significant. Systolic BP was similar in vehicle and ANP(4-23)-treated mice. These data suggest that: 1. Pharmacologic blockade of NPRC may be useful for treating glomerular diseases such as FSGS, and 2. Treatment outcomes might be improved by optimizing NPRC blockade to inhibit
natriuretic peptide clearance more effectively.