The cardiac
natriuretic peptides (NPs), atrial NP and B-type NP, regulate fluid homeostasis and arterial BP through renal actions involving increased GFR and vascular and tubular effects.
Guanylyl cyclase-A (GC-A), the transmembrane cGMP-producing receptor shared by these
peptides, is expressed in different renal cell types, including podocytes, where its function is unclear. To study the effects of NPs on podocytes, we generated mice with a podocyte-specific knockout of GC-A (Podo-GC-A KO). Despite the marked reduction of GC-A
mRNA in GC-A KO podocytes to 1% of the control level, Podo-GC-A KO mice and control littermates did not differ in BP, GFR, or natriuresis under baseline conditions. Moreover, infusion of synthetic NPs similarly increased the GFR and renal perfusion in both genotypes. Administration of the
mineralocorticoid deoxycorticosterone-
acetate (
DOCA) in combination with high
salt intake induced arterial
hypertension of similar magnitude in Podo-GC-A KO mice and controls. However, only Podo-GC-A KO mice developed massive
albuminuria (controls: 35-fold; KO: 5400-fold versus baseline),
hypoalbuminemia, reduced GFR, and marked glomerular damage. Furthermore,
DOCA treatment led to decreased expression of the slit diaphragm-associated
proteins podocin,
nephrin, and synaptopodin and to enhanced transient receptor potential canonical 6 (
TRPC6) channel expression and
ATP-induced
calcium influx in podocytes of Podo-GC-A KO mice. Concomitant treatment of Podo-GC-A KO mice with the TRPC channel blocker
SKF96365 markedly ameliorated
albuminuria and glomerular damage in response to
DOCA. In conclusion, the physiologic effects of NPs on GFR and natriuresis do not involve podocytes. However, NP/GC-A/cGMP signaling protects podocyte integrity under pathologic conditions, most likely by suppression of TRPC channels.