Discovery of endoplasmic reticulum calcium stabilizers to rescue ER-stressed podocytes in nephrotic syndrome
Emerging evidence has established primary nephrotic syndrome (NS), including focal segmental glomerulosclerosis (FSGS), as a primary podocytopathy. Despite the underlying importance of podocyte endoplasmic reticulum (ER) stress in the pathogenesis of NS, no treatment currently targets the podocyte ER. In our monogenic podocyte ER stress-induced NS/FSGS mouse model, the podocyte type 2 ryanodine receptor (RyR2)/calcium release channel on the ER was phosphorylated, resulting in ER calcium leak and cytosolic calcium elevation. The altered intracellular calcium homeostasis led to activation of calcium-dependent cytosolic protease calpain 2 and cleavage of its important downstream substrates, including the apoptotic molecule procaspase 12 and podocyte cytoskeletal protein talin 1. Importantly, a chemical compound, K201, can block RyR2-Ser2808 phosphorylation-mediated ER calcium depletion and podocyte injury in ER-stressed podocytes, as well as inhibit albuminuria in our NS model. In addition, we discovered that mesencephalic astrocyte-derived neurotrophic factor (MANF) can revert defective RyR2-induced ER calcium leak, a bioactivity for this ER stress-responsive protein. Thus, podocyte RyR2 remodeling contributes to ER stress-induced podocyte injury. K201 and MANF could be promising therapies for the treatment of podocyte ER stress-induced NS/FSGS.
| Errataetall: |
CommentIn: Nat Rev Nephrol. 2019 Sep;15(9):528. - PMID 31292538 |
|---|---|
| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2019 |
|---|---|
| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:116 |
|---|---|
| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 116(2019), 28 vom: 09. Juli, Seite 14154-14163 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Park, Sun-Ji [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 30.03.2020 Date Revised 13.12.2023 published: Print-Electronic CommentIn: Nat Rev Nephrol. 2019 Sep;15(9):528. - PMID 31292538 Citation Status MEDLINE |
|---|
| doi: |
10.1073/pnas.1813580116 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM298497204 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM298497204 | ||
| 003 | DE-627 | ||
| 005 | 20231227130040.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2019 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1073/pnas.1813580116 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1224.xml |
| 035 | |a (DE-627)NLM298497204 | ||
| 035 | |a (NLM)31235574 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Park, Sun-Ji |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Discovery of endoplasmic reticulum calcium stabilizers to rescue ER-stressed podocytes in nephrotic syndrome |
| 264 | 1 | |c 2019 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 30.03.2020 | ||
| 500 | |a Date Revised 13.12.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: Nat Rev Nephrol. 2019 Sep;15(9):528. - PMID 31292538 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Emerging evidence has established primary nephrotic syndrome (NS), including focal segmental glomerulosclerosis (FSGS), as a primary podocytopathy. Despite the underlying importance of podocyte endoplasmic reticulum (ER) stress in the pathogenesis of NS, no treatment currently targets the podocyte ER. In our monogenic podocyte ER stress-induced NS/FSGS mouse model, the podocyte type 2 ryanodine receptor (RyR2)/calcium release channel on the ER was phosphorylated, resulting in ER calcium leak and cytosolic calcium elevation. The altered intracellular calcium homeostasis led to activation of calcium-dependent cytosolic protease calpain 2 and cleavage of its important downstream substrates, including the apoptotic molecule procaspase 12 and podocyte cytoskeletal protein talin 1. Importantly, a chemical compound, K201, can block RyR2-Ser2808 phosphorylation-mediated ER calcium depletion and podocyte injury in ER-stressed podocytes, as well as inhibit albuminuria in our NS model. In addition, we discovered that mesencephalic astrocyte-derived neurotrophic factor (MANF) can revert defective RyR2-induced ER calcium leak, a bioactivity for this ER stress-responsive protein. Thus, podocyte RyR2 remodeling contributes to ER stress-induced podocyte injury. K201 and MANF could be promising therapies for the treatment of podocyte ER stress-induced NS/FSGS | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, N.I.H., Intramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a ER calcium stabilizer | |
| 650 | 4 | |a K201 | |
| 650 | 4 | |a endoplasmic reticulum stress | |
| 650 | 4 | |a podocytes | |
| 650 | 4 | |a type 2 ryanodine receptor | |
| 650 | 7 | |a MANF protein, mouse |2 NLM | |
| 650 | 7 | |a Nerve Growth Factors |2 NLM | |
| 650 | 7 | |a Ryanodine Receptor Calcium Release Channel |2 NLM | |
| 650 | 7 | |a Talin |2 NLM | |
| 650 | 7 | |a Thiazepines |2 NLM | |
| 650 | 7 | |a ryanodine receptor 2. mouse |2 NLM | |
| 650 | 7 | |a Tln1 protein, mouse |2 NLM | |
| 650 | 7 | |a K201 compound |2 NLM | |
| 650 | 7 | |a 0I621Y6R4Q |2 NLM | |
| 650 | 7 | |a Calpain |2 NLM | |
| 650 | 7 | |a EC 3.4.22.- |2 NLM | |
| 650 | 7 | |a Capn2 protein, mouse |2 NLM | |
| 650 | 7 | |a EC 3.4.22.53 |2 NLM | |
| 650 | 7 | |a Calcium |2 NLM | |
| 650 | 7 | |a SY7Q814VUP |2 NLM | |
| 700 | 1 | |a Kim, Yeawon |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Shyh-Ming |e verfasserin |4 aut | |
| 700 | 1 | |a Henderson, Mark J |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Lindahl, Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Urano, Fumihiko |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Ying Maggie |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Proceedings of the National Academy of Sciences of the United States of America |d 1915 |g 116(2019), 28 vom: 09. Juli, Seite 14154-14163 |w (DE-627)NLM000008982 |x 1091-6490 |7 nnns |
| 773 | 1 | 8 | |g volume:116 |g year:2019 |g number:28 |g day:09 |g month:07 |g pages:14154-14163 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1073/pnas.1813580116 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 116 |j 2019 |e 28 |b 09 |c 07 |h 14154-14163 | ||