TY - JOUR
T1 - Physiologic regulation of systemic klotho levels by renal casr signaling in response to casr ligands and pho
AU - Yoon, Joonho
AU - Liu, Zhenan
AU - Lee, Eunyoung
AU - Liu, Liping
AU - Ferre, Silvia
AU - Pastor, Johanne
AU - Zhang, Jianning
AU - Moe, Orson W.
AU - Chang, Audrey N.
AU - Tyler Miller, R.
N1 - Funding Information:
Funders: National Institutes of Health, (Grant / Award Number: 'DK081423','DK083592','DK091392','P30 DK-079328') Jane and Charles Pak Foundation, (Grant / Award Number: ) U.S. Department of Veterans Affairs, (Grant / Award Number: 'BX004691') Financial Disclosure: No L. Liu is employed by Reata pharmaceutical. R. Miller reports Consultancy Agreements with NIH (NIDDK), JDRF, ASN; Patents and Inventions for Ca receptor antibody with University of Florida; and Scientific Advisor or Membership with NIH study sections, JDRF Study Section, Ackerman Center for Holocaust studies, UT Dallas. O. Moe reports Consultancy Agreements with Allena Pharmaceutical, Alnylam, Dicernal Honoraria from Allena Pharmaceutical, Alnylam, and Dicerna - Consultation Fees; and Scientific Advisor or Membership as Editor of Seldin Giebisch The Kidney, and Editor of Current Opinion of Nephrology and Hypertension. All remaining authors have nothing to disclose.
Publisher Copyright:
© 2021 American Society of Nephrology. All rights reserved.
PY - 2021/12
Y1 - 2021/12
N2 - Background: The kidney is the source of sKlotho and kidney-specific loss of Klotho leads to a phenotype resembling the premature multi-organ failure phenotype in Klothohypomorphic mice (kl/kl mice). Klotho and the Ca-sensing receptor (CaSR) are highly expressed in the distal convoluted tubule (DCT). The physiologic mechanisms that regulate sKlotho levels are unknown. Methods: We measured sKlotho in WT and tubule-specific CaSR-/-(TS-CaSR-/-) mice treated with calcimimetics, alkali, or acid, and Klotho shed from minced mouse kidneys, as well as from HEK-293 cells expressing the CaSR and Klotho, in response to calcimimetics, calcilytics, alkalotic and acidic pH, and ADAM protease inhibitors. The CaSR, Klotho, and ADAM10 were imaged in mouse kidneys and cell expression systems using confocal microscopy. Results: The CaSR, Klotho, and ADAM10 co-localize on the baso-lateral membrane of the DCT. Calcimimetics and HCO3 increase serum sKlotho levels in WT but not in CaSR-/-mice and acid pH suppresses sKlotho levels in WT mice. In minced kidneys and cultured cells, CaSR activation with high Ca, calcimimetics, or alkali increase shed Klotho levels via ADAM10, as demonstrated using the ADAM10 inhibitor GI254023X and siRNA. In cultured cells the CaSR, Klotho, and ADAM10 form cell surface aggregates that disperse following CaSR activation. Conclusions: We identify a novel physiologic mechanism for regulation of sKlotho levels by the renal CaSR-ADAM10-Klotho pathway. We show that CaSR activators, including alkali, increase renal CaSR-stimulated Klotho shedding and predict that this mechanism is relevant to the effects of acidosis and alkali therapy on CKD progression.
AB - Background: The kidney is the source of sKlotho and kidney-specific loss of Klotho leads to a phenotype resembling the premature multi-organ failure phenotype in Klothohypomorphic mice (kl/kl mice). Klotho and the Ca-sensing receptor (CaSR) are highly expressed in the distal convoluted tubule (DCT). The physiologic mechanisms that regulate sKlotho levels are unknown. Methods: We measured sKlotho in WT and tubule-specific CaSR-/-(TS-CaSR-/-) mice treated with calcimimetics, alkali, or acid, and Klotho shed from minced mouse kidneys, as well as from HEK-293 cells expressing the CaSR and Klotho, in response to calcimimetics, calcilytics, alkalotic and acidic pH, and ADAM protease inhibitors. The CaSR, Klotho, and ADAM10 were imaged in mouse kidneys and cell expression systems using confocal microscopy. Results: The CaSR, Klotho, and ADAM10 co-localize on the baso-lateral membrane of the DCT. Calcimimetics and HCO3 increase serum sKlotho levels in WT but not in CaSR-/-mice and acid pH suppresses sKlotho levels in WT mice. In minced kidneys and cultured cells, CaSR activation with high Ca, calcimimetics, or alkali increase shed Klotho levels via ADAM10, as demonstrated using the ADAM10 inhibitor GI254023X and siRNA. In cultured cells the CaSR, Klotho, and ADAM10 form cell surface aggregates that disperse following CaSR activation. Conclusions: We identify a novel physiologic mechanism for regulation of sKlotho levels by the renal CaSR-ADAM10-Klotho pathway. We show that CaSR activators, including alkali, increase renal CaSR-stimulated Klotho shedding and predict that this mechanism is relevant to the effects of acidosis and alkali therapy on CKD progression.
KW - ADAM10
KW - Calcium sensing receptor
KW - Distal convoluted tubule
KW - Kidney
KW - Klotho
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UR - http://www.scopus.com/inward/citedby.url?scp=85120618917&partnerID=8YFLogxK
U2 - 10.1681/ASN.2021020276
DO - 10.1681/ASN.2021020276
M3 - Article
C2 - 34551996
AN - SCOPUS:85120618917
SN - 1046-6673
VL - 32
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 12
ER -