Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models

Mario Schiffer, Beina Teng, Changkyu Gu, Valentina A. Shchedrina, Marina Kasaikina, Vincent A. Pham, Nils Hanke, Song Rong, Faikah Gueler, Patricia Schroder, Irini Tossidou, Joon Keun Park, Lynne Staggs, Hermann Haller, Sergej Erschow, Denise Hilfiker-Kleiner, Changli Wei, Chuang Chen, Nicholas Tardi, Samy HakroushMartin K. Selig, Aleksandr Vasilyev, Sandra M Merscher-gomez, Jochen Reiser, Sanja Sever

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Dysregulation of the actin cytoskeleton in podocytes represents a common pathway in the pathogenesis of proteinuria across a spectrum of chronic kidney diseases (CKD). The GTPase dynamin has been implicated in the maintenance of cellular architecture in podocytes through its direct interaction with actin. Furthermore, the propensity of dynamin to oligomerize into higher-order structures in an actin-dependent manner and to cross-link actin microfilaments into higher-order structures has been correlated with increased actin polymerization and global organization of the actin cytoskeleton in the cell. We found that use of the small molecule Bis-T-23, which promotes actin-dependent dynamin oligomerization and thus increased actin polymerization in injured podocytes, was sufficient to improve renal health in diverse models of both transient kidney disease and CKD. In particular, administration of Bis-T-23 in these renal disease models restored the normal ultrastructure of podocyte foot processes, lowered proteinuria, lowered collagen IV deposits in the mesangial matrix, diminished mesangial matrix expansion and extended lifespan. These results further establish that alterations in the actin cytoskeleton of kidney podocytes is a common hallmark of CKD, while also underscoring the substantial regenerative potential of injured glomeruli and identifying the oligomerization cycle of dynamin as an attractive potential therapeutic target to treat CKD.

Original languageEnglish (US)
Pages (from-to)601-609
Number of pages9
JournalNature Medicine
Volume21
Issue number6
DOIs
StatePublished - May 11 2015

Fingerprint

Dynamins
Podocytes
Oligomerization
Chronic Renal Insufficiency
Actins
Animals
Actin Cytoskeleton
Animal Models
Pharmacology
Kidney
Proteinuria
Polymerization
GTP Phosphohydrolases
Kidney Diseases
Collagen
Maintenance
Health
Deposits

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Schiffer, M., Teng, B., Gu, C., Shchedrina, V. A., Kasaikina, M., Pham, V. A., ... Sever, S. (2015). Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models. Nature Medicine, 21(6), 601-609. https://doi.org/10.1038/nm.3843

Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models. / Schiffer, Mario; Teng, Beina; Gu, Changkyu; Shchedrina, Valentina A.; Kasaikina, Marina; Pham, Vincent A.; Hanke, Nils; Rong, Song; Gueler, Faikah; Schroder, Patricia; Tossidou, Irini; Park, Joon Keun; Staggs, Lynne; Haller, Hermann; Erschow, Sergej; Hilfiker-Kleiner, Denise; Wei, Changli; Chen, Chuang; Tardi, Nicholas; Hakroush, Samy; Selig, Martin K.; Vasilyev, Aleksandr; Merscher-gomez, Sandra M; Reiser, Jochen; Sever, Sanja.

In: Nature Medicine, Vol. 21, No. 6, 11.05.2015, p. 601-609.

Research output: Contribution to journalArticle

Schiffer, M, Teng, B, Gu, C, Shchedrina, VA, Kasaikina, M, Pham, VA, Hanke, N, Rong, S, Gueler, F, Schroder, P, Tossidou, I, Park, JK, Staggs, L, Haller, H, Erschow, S, Hilfiker-Kleiner, D, Wei, C, Chen, C, Tardi, N, Hakroush, S, Selig, MK, Vasilyev, A, Merscher-gomez, SM, Reiser, J & Sever, S 2015, 'Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models', Nature Medicine, vol. 21, no. 6, pp. 601-609. https://doi.org/10.1038/nm.3843
Schiffer, Mario ; Teng, Beina ; Gu, Changkyu ; Shchedrina, Valentina A. ; Kasaikina, Marina ; Pham, Vincent A. ; Hanke, Nils ; Rong, Song ; Gueler, Faikah ; Schroder, Patricia ; Tossidou, Irini ; Park, Joon Keun ; Staggs, Lynne ; Haller, Hermann ; Erschow, Sergej ; Hilfiker-Kleiner, Denise ; Wei, Changli ; Chen, Chuang ; Tardi, Nicholas ; Hakroush, Samy ; Selig, Martin K. ; Vasilyev, Aleksandr ; Merscher-gomez, Sandra M ; Reiser, Jochen ; Sever, Sanja. / Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models. In: Nature Medicine. 2015 ; Vol. 21, No. 6. pp. 601-609.
@article{2d78d64958b54aa4ba19f5b0f1c6eac2,
title = "Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models",
abstract = "Dysregulation of the actin cytoskeleton in podocytes represents a common pathway in the pathogenesis of proteinuria across a spectrum of chronic kidney diseases (CKD). The GTPase dynamin has been implicated in the maintenance of cellular architecture in podocytes through its direct interaction with actin. Furthermore, the propensity of dynamin to oligomerize into higher-order structures in an actin-dependent manner and to cross-link actin microfilaments into higher-order structures has been correlated with increased actin polymerization and global organization of the actin cytoskeleton in the cell. We found that use of the small molecule Bis-T-23, which promotes actin-dependent dynamin oligomerization and thus increased actin polymerization in injured podocytes, was sufficient to improve renal health in diverse models of both transient kidney disease and CKD. In particular, administration of Bis-T-23 in these renal disease models restored the normal ultrastructure of podocyte foot processes, lowered proteinuria, lowered collagen IV deposits in the mesangial matrix, diminished mesangial matrix expansion and extended lifespan. These results further establish that alterations in the actin cytoskeleton of kidney podocytes is a common hallmark of CKD, while also underscoring the substantial regenerative potential of injured glomeruli and identifying the oligomerization cycle of dynamin as an attractive potential therapeutic target to treat CKD.",
author = "Mario Schiffer and Beina Teng and Changkyu Gu and Shchedrina, {Valentina A.} and Marina Kasaikina and Pham, {Vincent A.} and Nils Hanke and Song Rong and Faikah Gueler and Patricia Schroder and Irini Tossidou and Park, {Joon Keun} and Lynne Staggs and Hermann Haller and Sergej Erschow and Denise Hilfiker-Kleiner and Changli Wei and Chuang Chen and Nicholas Tardi and Samy Hakroush and Selig, {Martin K.} and Aleksandr Vasilyev and Merscher-gomez, {Sandra M} and Jochen Reiser and Sanja Sever",
year = "2015",
month = "5",
day = "11",
doi = "10.1038/nm.3843",
language = "English (US)",
volume = "21",
pages = "601--609",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "6",

}

TY - JOUR

T1 - Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models

AU - Schiffer, Mario

AU - Teng, Beina

AU - Gu, Changkyu

AU - Shchedrina, Valentina A.

AU - Kasaikina, Marina

AU - Pham, Vincent A.

AU - Hanke, Nils

AU - Rong, Song

AU - Gueler, Faikah

AU - Schroder, Patricia

AU - Tossidou, Irini

AU - Park, Joon Keun

AU - Staggs, Lynne

AU - Haller, Hermann

AU - Erschow, Sergej

AU - Hilfiker-Kleiner, Denise

AU - Wei, Changli

AU - Chen, Chuang

AU - Tardi, Nicholas

AU - Hakroush, Samy

AU - Selig, Martin K.

AU - Vasilyev, Aleksandr

AU - Merscher-gomez, Sandra M

AU - Reiser, Jochen

AU - Sever, Sanja

PY - 2015/5/11

Y1 - 2015/5/11

N2 - Dysregulation of the actin cytoskeleton in podocytes represents a common pathway in the pathogenesis of proteinuria across a spectrum of chronic kidney diseases (CKD). The GTPase dynamin has been implicated in the maintenance of cellular architecture in podocytes through its direct interaction with actin. Furthermore, the propensity of dynamin to oligomerize into higher-order structures in an actin-dependent manner and to cross-link actin microfilaments into higher-order structures has been correlated with increased actin polymerization and global organization of the actin cytoskeleton in the cell. We found that use of the small molecule Bis-T-23, which promotes actin-dependent dynamin oligomerization and thus increased actin polymerization in injured podocytes, was sufficient to improve renal health in diverse models of both transient kidney disease and CKD. In particular, administration of Bis-T-23 in these renal disease models restored the normal ultrastructure of podocyte foot processes, lowered proteinuria, lowered collagen IV deposits in the mesangial matrix, diminished mesangial matrix expansion and extended lifespan. These results further establish that alterations in the actin cytoskeleton of kidney podocytes is a common hallmark of CKD, while also underscoring the substantial regenerative potential of injured glomeruli and identifying the oligomerization cycle of dynamin as an attractive potential therapeutic target to treat CKD.

AB - Dysregulation of the actin cytoskeleton in podocytes represents a common pathway in the pathogenesis of proteinuria across a spectrum of chronic kidney diseases (CKD). The GTPase dynamin has been implicated in the maintenance of cellular architecture in podocytes through its direct interaction with actin. Furthermore, the propensity of dynamin to oligomerize into higher-order structures in an actin-dependent manner and to cross-link actin microfilaments into higher-order structures has been correlated with increased actin polymerization and global organization of the actin cytoskeleton in the cell. We found that use of the small molecule Bis-T-23, which promotes actin-dependent dynamin oligomerization and thus increased actin polymerization in injured podocytes, was sufficient to improve renal health in diverse models of both transient kidney disease and CKD. In particular, administration of Bis-T-23 in these renal disease models restored the normal ultrastructure of podocyte foot processes, lowered proteinuria, lowered collagen IV deposits in the mesangial matrix, diminished mesangial matrix expansion and extended lifespan. These results further establish that alterations in the actin cytoskeleton of kidney podocytes is a common hallmark of CKD, while also underscoring the substantial regenerative potential of injured glomeruli and identifying the oligomerization cycle of dynamin as an attractive potential therapeutic target to treat CKD.

UR - http://www.scopus.com/inward/record.url?scp=84930752224&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84930752224&partnerID=8YFLogxK

U2 - 10.1038/nm.3843

DO - 10.1038/nm.3843

M3 - Article

C2 - 25962121

AN - SCOPUS:84930752224

VL - 21

SP - 601

EP - 609

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 6

ER -