Injured Podocytes Are Sensitized to Angiotensin II-Induced Calcium Signaling
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Injured Podocytes Are Sensitized to Angiotensin II-Induced Calcium Signaling. / Binz-Lotter, Julia; Jüngst, Christian; Rinschen, Markus M; Koehler, Sybille; Zentis, Peter; Schauss, Astrid; Schermer, Bernhard; Benzing, Thomas; Hackl, Matthias J.
in: J AM SOC NEPHROL, Jahrgang 31, Nr. 3, 03.2020, S. 532-542.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Injured Podocytes Are Sensitized to Angiotensin II-Induced Calcium Signaling
AU - Binz-Lotter, Julia
AU - Jüngst, Christian
AU - Rinschen, Markus M
AU - Koehler, Sybille
AU - Zentis, Peter
AU - Schauss, Astrid
AU - Schermer, Bernhard
AU - Benzing, Thomas
AU - Hackl, Matthias J
N1 - Copyright © 2020 by the American Society of Nephrology.
PY - 2020/3
Y1 - 2020/3
N2 - BACKGROUND: Inhibition of angiotensin II (AngII) signaling, a therapeutic mainstay of glomerular kidney diseases, is thought to act primarily through regulating glomerular blood flow and reducing filtration pressure. Although extravascular actions of AngII have been suggested, a direct effect of AngII on podocytes has not been demonstrated in vivo.METHODS: To study the effects of AngII on podocyte calcium levels in vivo, we used intravital microscopy of the kidney in mice expressing the calcium indicator protein GCaMP3.RESULTS: In healthy animals, podocytes displayed limited responsiveness to AngII stimulation. In contrast, in animals subjected to either adriamycin-induced acute chemical injury or genetic deletion of the podocin-encoding gene Nphs2, the consequent podocyte damage and proteinuria rendered the cells responsive to AngII and resulted in AngII-induced calcium transients in significantly more podocytes. The angiotensin type 1 receptor blocker losartan could fully inhibit this response. Also, responsiveness to AngII was at least partly mediated through the transient receptor potential channel 6, which has been implicated in podocyte calcium handling. Interestingly, loss of a single Nphs2 allele also increased podocytes' responsiveness to AngII signaling. This direct effect of AngII on injured podocytes results in increased calcium transients, which can further aggravate the underlying kidney disease.CONCLUSIONS: Our discovery that podocytes become sensitized to AngII-induced calcium signaling upon injury might explain results from large, randomized, controlled trials in which improved renal outcomes occur only in the subgroup of patients with proteinuria, indicating podocyte damage. Our findings also emphasize the need to treat every patient with a glomerular disease with either an angiotensin-converting enzyme inhibitor or an angiotensin type 1 receptor blocker.
AB - BACKGROUND: Inhibition of angiotensin II (AngII) signaling, a therapeutic mainstay of glomerular kidney diseases, is thought to act primarily through regulating glomerular blood flow and reducing filtration pressure. Although extravascular actions of AngII have been suggested, a direct effect of AngII on podocytes has not been demonstrated in vivo.METHODS: To study the effects of AngII on podocyte calcium levels in vivo, we used intravital microscopy of the kidney in mice expressing the calcium indicator protein GCaMP3.RESULTS: In healthy animals, podocytes displayed limited responsiveness to AngII stimulation. In contrast, in animals subjected to either adriamycin-induced acute chemical injury or genetic deletion of the podocin-encoding gene Nphs2, the consequent podocyte damage and proteinuria rendered the cells responsive to AngII and resulted in AngII-induced calcium transients in significantly more podocytes. The angiotensin type 1 receptor blocker losartan could fully inhibit this response. Also, responsiveness to AngII was at least partly mediated through the transient receptor potential channel 6, which has been implicated in podocyte calcium handling. Interestingly, loss of a single Nphs2 allele also increased podocytes' responsiveness to AngII signaling. This direct effect of AngII on injured podocytes results in increased calcium transients, which can further aggravate the underlying kidney disease.CONCLUSIONS: Our discovery that podocytes become sensitized to AngII-induced calcium signaling upon injury might explain results from large, randomized, controlled trials in which improved renal outcomes occur only in the subgroup of patients with proteinuria, indicating podocyte damage. Our findings also emphasize the need to treat every patient with a glomerular disease with either an angiotensin-converting enzyme inhibitor or an angiotensin type 1 receptor blocker.
KW - Angiotensin-Converting Enzyme Inhibitors/pharmacology
KW - Animals
KW - Calcium Signaling/drug effects
KW - Cells, Cultured
KW - Disease Models, Animal
KW - Glomerulonephritis/metabolism
KW - Humans
KW - Intracellular Signaling Peptides and Proteins/metabolism
KW - Kidney Glomerulus/drug effects
KW - Losartan/pharmacology
KW - Male
KW - Membrane Proteins/metabolism
KW - Mice
KW - Podocytes/drug effects
KW - Proteinuria/metabolism
KW - Random Allocation
KW - Receptor, Angiotensin, Type 1/drug effects
KW - Reference Values
U2 - 10.1681/ASN.2019020109
DO - 10.1681/ASN.2019020109
M3 - SCORING: Journal article
C2 - 31924670
VL - 31
SP - 532
EP - 542
JO - J AM SOC NEPHROL
JF - J AM SOC NEPHROL
SN - 1046-6673
IS - 3
ER -
