Universität zu Köln

Binz-Lotter, Julia, Juengst, Christian, Rinschen, Markus M., Koehler, Sybille, Zentis, Peter ORCID: 0000-0002-6999-132X, Schauss, Astrid, Schermer, Bernhard, Benzing, Thomas and Hackl, Matthias J. (2020). Injured Podocytes Are Sensitized to Angiotensin II-Induced Calcium Signaling. J. Am. Soc. Nephrol., 31 (3). S. 532 - 543. WASHINGTON: AMER SOC NEPHROLOGY. ISSN 1533-3450

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Abstract

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 Angll 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 podocinencoding gene Nphs2, the consequent podocyte damage and proteinuria rendered the cells responsive to Angll 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Binz-Lotter, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Juengst, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Rinschen, Markus M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Koehler, Sybille UNSPECIFIED UNSPECIFIED UNSPECIFIED Zentis, Peter UNSPECIFIED orcid.org/0000-0002-6999-132X UNSPECIFIED Schauss, Astrid UNSPECIFIED UNSPECIFIED UNSPECIFIED Schermer, Bernhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Benzing, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Hackl, Matthias J. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-343151
DOI:	10.1681/ASN.2019020109
Journal or Publication Title:	J. Am. Soc. Nephrol.
Volume:	31
Number:	3
Page Range:	S. 532 - 543
Date:	2020
Publisher:	AMER SOC NEPHROLOGY
Place of Publication:	WASHINGTON
ISSN:	1533-3450
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language BLOOD-PRESSURE CONTROL; GLOMERULAR-FILTRATION; PROTECTS PODOCYTES; RENAL-DISEASE; GLOMERULOSCLEROSIS; INCREASES; CHANNELS; PODOCIN Multiple languages Urology & Nephrology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/34315