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.
Aim Natriuretic peptides, BNP and ANP increase renal blood flow in experimental animals. The signalling pathway in human kidney vasculature is unknown. It was hypothesized that BNP and ANP cause endothelium‐independent relaxation of human intrarenal arteries by vascular natriuretic peptide receptor‐A, but not ‐B and ‐C, which is mimicked by agonists of soluble guanylyl cyclase sGC. Methods Human (n = 54, diameter: 665 ± 29 µm 95% CI) and control murine intrarenal arteries (n = 83, diameter 300 ± 6 µm 95% CI) were dissected and used for force recording by four‐channel wire myography. Arterial segments were pre‐contracted, then subjected to increasing concentrations of BNP, ANP, phosphodiesterase 5‐inhibitor sildenafil, sGC‐activator BAY 60‐2770 and ‐stimulator BAY 41‐2272. Endothelial nitric oxide synthase (eNOS) dependence was examined by use of L‐NAME and eNOS knockout respectively. Molecular targets (NPR A‐C, sGC, phosphodiesterase‐5 and neprilysin) were mapped by PCR, immunohistochemistry and RNAscope. Results BNP, ANP, sildenafil, sGC‐activation and ‐stimulation caused concentration‐dependent relaxation of human and murine intrarenal arteries. BNP responses were independent of eNOS and were not potentiated by low concentration of phosphodiesterase‐5‐inhibitor, sGC‐stimulator or NPR‐C blocker. PCR showed NPR‐A and C, phosphodiesterase‐5, neprilysin and sGC mRNA in renal arteries. NPR‐A mRNA and protein was observed in vascular smooth muscle and endothelial cells in arteries, podocytes, Bowmans capsule and vasa recta. NPR‐C was observed in tubules, glomeruli and vasculature. Conclusion Activation of transmembrane NPR‐A and soluble guanylyl cyclase relax human preglomerular arteries similarly to phosphodiestase‐5 inhibition. The human renal arterial bed relaxes in response to cGMP pathway.
The inhibition of renal SGLT2 glucose reabsorption has proven its therapeutic efficacy in chronic kidney disease. SGLT2 inhibitors (SGLTi) have been intensively studied in rodent models to identify the mechanisms of SGLT2i-mediated nephroprotection. So far, the overwhelming effects from clinical trials, could only partially be reproduced in rodent models of renal injury. However, a commonly disregarded observation from these studies, is the increase in kidney weight after SGLT2i administration. Increased kidney mass often relies on tubular growth in response to reabsorption overload during glomerular hyperfiltration. Since SGLT2i suppress hyperfiltration but concomitantly increase renal weight, it seems likely that SGLT2i have a growth promoting effect on the kidney itself, independent of GFR control. This study aimed to investigate the effect of SGLT2i on kidney growth in wildtype animals, to identify enlarged nephron segments and classify the size increase as hypertrophic/hyperplastic growth or cell swelling. SGLT2i empagliflozin increased kidney weight in wildtype mice by 13% compared to controls, while bodyweight and other organs were not affected. The enlarged nephron segments were identified as SGLT2-negative distal segments of proximal tubules and as collecting ducts by histological quantification of tubular cell area. In both segments protein/DNA ratio, a marker for hypertrophic growth, was increased by 6% and 12% respectively, while tubular nuclei number (hyperplasia) was unchanged by empagliflozin. SGLT2-inhibition in early proximal tubules induces a shift of NaCl resorption along the nephron causing compensatory NaCl and H2O reabsorption and presumably cell growth in downstream segments. Consistently, in collecting ducts of empagliflozin-treated mice, mRNA expression of the Na+-channel ENaC and the H2O-channels Aqp-2/Aqp-3 were increased. In addition, the hypoxia marker Hif1α was found increased in intercalated cells of the collecting duct together with evidence for increased proton secretion, as indicated by upregulation of carbonic anhydrases and acidified urine pH in empagliflozin-treated animals. In summary, these data show that SGLT2i induce cell enlargement by hypertrophic growth and possibly cell swelling in healthy kidneys, probably as a result of compensatory glucose, NaCl and H2O hyperreabsorption of SGLT2-negative segments. Particularly affected are the SGLT2-negative proximal tubules (S3) and the collecting duct, areas of low O2 availability.
Background: Excessive desmoplasia is a typical feature of pancreatic ductal adenocarcinoma (PDAC) and is highly associated with an aggressive tumor phenotype. The main cell population contributing to the stromal response consists of pancreatic stellate cells (PSCs). Periostin, an extracellular matrix protein (ECM), produced by activated PSCs has been shown to have anti-apoptotic and growth-stimulatory effects on pancreatic tumor cells as well as the ability to create a metastatic niche in the secondary target organ. The main signaling route by which periostin mediates its effects is the integrin signaling pathway. Through binding to different integrin subunits the focal adhesion kinase (FAK) gets phosphorylated and downstream signaling pathways such as RAS/ERK/MEK become additionally activated. Aim: Analyzing the function of periostin in early pancreatic carcinogenesis as well as metastatic spread. Methods: A conditional tumor mouse model, expressing oncogenic KrasG12D under the control of a pancreas specific Ptf1a promoter was crossbred with Postn global knockout mice (p48Cre/+;LSL-KrasG12D/+;Postn-/-) and early tumor development was analyzed at two, three and six months of age. In a second approach, a tumor-promoting inflammatory stromal reaction was induced by cerulein injections in p48Cre/+;LSL-KrasG12D/+ mice whereby one group of mice was additionally treated with a daily dose (30mg/kg) of FAK inhibitor. All mice were sacrificed after 7 days and HE staining was performed. Thirdly, to study metastasis formation, murine pancreatic tumor cells were injected into the tail vein of wild type, Postn+/- and Postn-/- mice. After 6 weeks target organs were collected for subsequent analyses. Results: In the early phases, p48Cre/+;LSL-KrasG12D/+;Postn-/- mice displayed less PanIN lesions, fewer atypical ductal structures and reduced proliferating cells. The inhibition of FAK-signaling blocked pancreatic tumorigenesis and absence of periostin abrogated metastatic spread. Conclusion: Periostin produced by the pancreatic stellate cell is necessary both for early carcinogenesis and metastatic spread. The effects of periostin can be antagonized by blocking its downstream pathway using FAK inhibitors. Citation Format: Simone Hausmann, Ivonne Regel, Anna Federlein, Pawel K. Mazur, Katja Steiger, Christoph W. Michalski, Mert Erkan, Jörg Kleeff. The role of periostin in pancreatic carcinogenesis and metastatic spread. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B08.
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