Universität zu Köln

Banki, Eszter, Fisi, Viktoria, Moser, Sandra, Wengi, Agnieszka, Carrel, Monique, Loffing-Cueni, Dominique, Penton, David, V. Kratschmar, Denise, Rizzo, Ludovica, Lienkamp, Soeren ORCID: 0000-0003-2963-6865, Odermatt, Alex, Rinschen, Markus M. and Loffing, Johannes (2021). Specific disruption of calcineurin-signaling in the distal convoluted tubule impacts the transcriptome and proteome, and causes hypomagnesemia and metabolic acidosis. Kidney Int., 100 (4). S. 850 - 870. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1523-1755

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Abstract

Adverse effects of calcineurin inhibitors (CNI), such as hypertension, hyperkalemia, acidosis, hypomagnesemia and hypercalciuria, have been linked to dysfunction of the distal convoluted tubule (DCT). To test this, we generated a mouse model with an inducible DCT-specific deletion of the calcineurin regulatory subunit B alpha (CnB1-KO). Three weeks after CnB1 deletion, these mice exhibited hypomagnesemia and acidosis, but no hypertension, hyperkalemia or hypercalciuria. Consistent with the hypomagnesemia, CnB1-KO mice showed a downregulation of proteins implicated in DCT magnesium transport, including TRPM6, CNNM2, SLC41A3 and parvalbumin but expression of calcium channel TRPV5 in the kidney was unchanged. The abundance of the chloride/bicarbonate exchanger pendrin was increased, likely explaining the acidosis. Plasma aldosterone levels, kidney renin expression, abundance of phosphorylated sodium chloride-cotransporter and abundance of the epithelial sodium channel were similar in control and CnB1-KO mice, consistent with a normal sodium balance. Long-term potassium homeostasis was maintained in CnB1-KO mice, but in-vivo and ex-vivo experiments indicated that CnB1 contributes to acute regulation of potassium balance and sodium chloride-cotransporter. Tacrolimus treatment of control and CnB1-KO mice demonstrated that CNI-related hypomagnesemia is linked to impaired calcineurinsignaling in DCT, while hypocalciuria and hyponatremia occur independently of CnB1 in DCT. Transcriptome and proteome analyses of isolated DCTs demonstrated that CnB1 deletion impacts the expression of several DCTspecific proteins and signaling pathways. Thus, our data support a critical role of calcineurin for DCT function and provide novel insights into the pathophysiology of CNI side effects and involved molecular players in the DCT.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Banki, Eszter UNSPECIFIED UNSPECIFIED UNSPECIFIED Fisi, Viktoria UNSPECIFIED UNSPECIFIED UNSPECIFIED Moser, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Wengi, Agnieszka UNSPECIFIED UNSPECIFIED UNSPECIFIED Carrel, Monique UNSPECIFIED UNSPECIFIED UNSPECIFIED Loffing-Cueni, Dominique UNSPECIFIED UNSPECIFIED UNSPECIFIED Penton, David UNSPECIFIED UNSPECIFIED UNSPECIFIED V. Kratschmar, Denise UNSPECIFIED UNSPECIFIED UNSPECIFIED Rizzo, Ludovica UNSPECIFIED UNSPECIFIED UNSPECIFIED Lienkamp, Soeren UNSPECIFIED orcid.org/0000-0003-2963-6865 UNSPECIFIED Odermatt, Alex UNSPECIFIED UNSPECIFIED UNSPECIFIED Rinschen, Markus M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Loffing, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-593584
DOI:	10.1016/j.kint.2021.06.030
Journal or Publication Title:	Kidney Int.
Volume:	100
Number:	4
Page Range:	S. 850 - 870
Date:	2021
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1523-1755
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SODIUM-CHLORIDE COTRANSPORTER; TACROLIMUS; CYCLOSPORINE; TRANSPORT; MICE; DEPHOSPHORYLATION; HYPERCALCIURIA; NETWORK; CALCIUM; CELLS Multiple languages Urology & Nephrology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59358