title: Natriuretic Peptide Receptor Guanylyl Cyclase-A in Podocytes is Renoprotective but Dispensable for Physiologic Renal Function.
abstract: 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.
authors.affiliation: Institutes of *Physiology and.
authors.forename: Janina
authors.initials: J
authors.lastname: Staffel
authors.affiliation: Institutes of *Physiology and.
authors.forename: Daniela
authors.initials: D
authors.lastname: Valletta
authors.affiliation: Institutes of *Physiology and.
authors.forename: Anna
authors.initials: A
authors.lastname: Federlein
authors.affiliation: Institutes of *Physiology and.
authors.forename: Katharina
authors.initials: K
authors.lastname: Ehm
authors.affiliation: Institutes of *Physiology and.
authors.forename: Regine
authors.initials: R
authors.lastname: Volkmann
authors.affiliation: Institutes of *Physiology and.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Füchsl
authors.affiliation: Anatomy, University of Regensburg, Regensburg, Germany; and.
authors.forename: Ralph
authors.initials: R
authors.lastname: Witzgall
authors.affiliation: Institute of Physiology, University of Würzburg, Würzburg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Kuhn
authors.affiliation: Institutes of *Physiology and frank.schweda@klinik.uni-regensburg.de.
authors.forename: Frank
authors.initials: F
authors.lastname: Schweda
mesh_terms: D000818:Animals; D005260:Female; D007668:Kidney / Q000502:physiology*; D007674:Kidney Diseases / Q000209:etiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D050199:Podocytes / Q000473:pathology / Q000502:physiology*; D017461:Receptors, Atrial Natriuretic Factor / Q000502:physiology*; D050052:TRPC Cation Channels / Q000502:physiology; D000074287:TRPC6 Cation Channel
chemical_list: D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A
keywords: albuminuria; cardiac natriuretic peptides; podocyte; progression of renal failure