Effects of erythropoietin receptor activity on angiogenesis, tubular injury, and fibrosis in acute kidney injury: A “U-shaped” relationship

Mingjun Shi, Brianna Flores, Peng Li, Nancy Gillings, Kathryn L. McMillan, Jianfeng Ye, Lily Jun Shen Huang, Sachdev S. Sidhu, Yong Ping Zhong, Maria T. Grompe, Philip Streeter, Orson W. Moe, Ming Chang Hu

Research output: Contribution to journalArticle

Abstract

The erythropoietin receptor (EpoR) is widely expressed but its renoprotective action is unexplored. To examine the role of EpoR in vivo in the kidney, we induced acute kidney injury (AKI) by ischemiareperfusion in mice with different EpoR bioactivities in the kidney. EpoR bioactivity was reduced by knockin of wild-type human EpoR, which is hypofunctional relative to murine EpoR, and a renal tubulespecific EpoR knockout. These mice had lower EPO/EpoR activity and lower autophagy flux in renal tubules. Upon AKI induction, they exhibited worse renal function and structural damage, more apoptosis at the acute stage (<7 days), and slower recovery with more tubulointerstitial fibrosis at the subacute stage (14 days). In contrast, mice with hyperactive EpoR signaling from knockin of a constitutively active human EpoR had higher autophagic flux, milder kidney damage, and better renal function at the acute stage but, surprisingly, worse tubulointerstitial fibrosis and renal function at the subacute stage. Either excess or deficient EpoR activity in the kidney was associated with abnormal peritubular capillaries and tubular hypoxia, creating a “U-shaped” relationship. The direct effects of EpoR on tubular cells were confirmed in vitro by a hydrogen peroxide model using primary cultured proximal tubule cells with different EpoR activities. In summary, normal erythropoietin (EPO)/EpoR signaling in renal tubules provides defense against renal tubular injury maintains the autophagy-apoptosis balance and peritubular capillary integrity. High and low EPO/EpoR bioactivities both lead to vascular defect, and high EpoR activity overides the tubular protective effects in AKI recovery.

Original languageEnglish (US)
Pages (from-to)F501-F516
JournalAmerican Journal of Physiology - Renal Physiology
Volume314
Issue number4
DOIs
StatePublished - Apr 1 2018

Fingerprint

Erythropoietin Receptors
Acute Kidney Injury
Fibrosis
Wounds and Injuries
Kidney
Erythropoietin
Autophagy
Apoptosis

Keywords

  • AKI
  • Autophagy
  • EpoR
  • Peritubular capillary
  • Tubulointerstitial fibrosis

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Effects of erythropoietin receptor activity on angiogenesis, tubular injury, and fibrosis in acute kidney injury : A “U-shaped” relationship. / Shi, Mingjun; Flores, Brianna; Li, Peng; Gillings, Nancy; McMillan, Kathryn L.; Ye, Jianfeng; Huang, Lily Jun Shen; Sidhu, Sachdev S.; Zhong, Yong Ping; Grompe, Maria T.; Streeter, Philip; Moe, Orson W.; Hu, Ming Chang.

In: American Journal of Physiology - Renal Physiology, Vol. 314, No. 4, 01.04.2018, p. F501-F516.

Research output: Contribution to journalArticle

Shi, M, Flores, B, Li, P, Gillings, N, McMillan, KL, Ye, J, Huang, LJS, Sidhu, SS, Zhong, YP, Grompe, MT, Streeter, P, Moe, OW & Hu, MC 2018, 'Effects of erythropoietin receptor activity on angiogenesis, tubular injury, and fibrosis in acute kidney injury: A “U-shaped” relationship', American Journal of Physiology - Renal Physiology, vol. 314, no. 4, pp. F501-F516. https://doi.org/10.1152/ajprenal.00306.2017
Shi, Mingjun ; Flores, Brianna ; Li, Peng ; Gillings, Nancy ; McMillan, Kathryn L. ; Ye, Jianfeng ; Huang, Lily Jun Shen ; Sidhu, Sachdev S. ; Zhong, Yong Ping ; Grompe, Maria T. ; Streeter, Philip ; Moe, Orson W. ; Hu, Ming Chang. / Effects of erythropoietin receptor activity on angiogenesis, tubular injury, and fibrosis in acute kidney injury : A “U-shaped” relationship. In: American Journal of Physiology - Renal Physiology. 2018 ; Vol. 314, No. 4. pp. F501-F516.
@article{16b6ae0818c74e9587104dbf0e883ab4,
title = "Effects of erythropoietin receptor activity on angiogenesis, tubular injury, and fibrosis in acute kidney injury: A “U-shaped” relationship",
abstract = "The erythropoietin receptor (EpoR) is widely expressed but its renoprotective action is unexplored. To examine the role of EpoR in vivo in the kidney, we induced acute kidney injury (AKI) by ischemiareperfusion in mice with different EpoR bioactivities in the kidney. EpoR bioactivity was reduced by knockin of wild-type human EpoR, which is hypofunctional relative to murine EpoR, and a renal tubulespecific EpoR knockout. These mice had lower EPO/EpoR activity and lower autophagy flux in renal tubules. Upon AKI induction, they exhibited worse renal function and structural damage, more apoptosis at the acute stage (<7 days), and slower recovery with more tubulointerstitial fibrosis at the subacute stage (14 days). In contrast, mice with hyperactive EpoR signaling from knockin of a constitutively active human EpoR had higher autophagic flux, milder kidney damage, and better renal function at the acute stage but, surprisingly, worse tubulointerstitial fibrosis and renal function at the subacute stage. Either excess or deficient EpoR activity in the kidney was associated with abnormal peritubular capillaries and tubular hypoxia, creating a “U-shaped” relationship. The direct effects of EpoR on tubular cells were confirmed in vitro by a hydrogen peroxide model using primary cultured proximal tubule cells with different EpoR activities. In summary, normal erythropoietin (EPO)/EpoR signaling in renal tubules provides defense against renal tubular injury maintains the autophagy-apoptosis balance and peritubular capillary integrity. High and low EPO/EpoR bioactivities both lead to vascular defect, and high EpoR activity overides the tubular protective effects in AKI recovery.",
keywords = "AKI, Autophagy, EpoR, Peritubular capillary, Tubulointerstitial fibrosis",
author = "Mingjun Shi and Brianna Flores and Peng Li and Nancy Gillings and McMillan, {Kathryn L.} and Jianfeng Ye and Huang, {Lily Jun Shen} and Sidhu, {Sachdev S.} and Zhong, {Yong Ping} and Grompe, {Maria T.} and Philip Streeter and Moe, {Orson W.} and Hu, {Ming Chang}",
year = "2018",
month = "4",
day = "1",
doi = "10.1152/ajprenal.00306.2017",
language = "English (US)",
volume = "314",
pages = "F501--F516",
journal = "American Journal of Physiology - Renal Fluid and Electrolyte Physiology",
issn = "1931-857X",
publisher = "American Physiological Society",
number = "4",

}

TY - JOUR

T1 - Effects of erythropoietin receptor activity on angiogenesis, tubular injury, and fibrosis in acute kidney injury

T2 - A “U-shaped” relationship

AU - Shi, Mingjun

AU - Flores, Brianna

AU - Li, Peng

AU - Gillings, Nancy

AU - McMillan, Kathryn L.

AU - Ye, Jianfeng

AU - Huang, Lily Jun Shen

AU - Sidhu, Sachdev S.

AU - Zhong, Yong Ping

AU - Grompe, Maria T.

AU - Streeter, Philip

AU - Moe, Orson W.

AU - Hu, Ming Chang

PY - 2018/4/1

Y1 - 2018/4/1

N2 - The erythropoietin receptor (EpoR) is widely expressed but its renoprotective action is unexplored. To examine the role of EpoR in vivo in the kidney, we induced acute kidney injury (AKI) by ischemiareperfusion in mice with different EpoR bioactivities in the kidney. EpoR bioactivity was reduced by knockin of wild-type human EpoR, which is hypofunctional relative to murine EpoR, and a renal tubulespecific EpoR knockout. These mice had lower EPO/EpoR activity and lower autophagy flux in renal tubules. Upon AKI induction, they exhibited worse renal function and structural damage, more apoptosis at the acute stage (<7 days), and slower recovery with more tubulointerstitial fibrosis at the subacute stage (14 days). In contrast, mice with hyperactive EpoR signaling from knockin of a constitutively active human EpoR had higher autophagic flux, milder kidney damage, and better renal function at the acute stage but, surprisingly, worse tubulointerstitial fibrosis and renal function at the subacute stage. Either excess or deficient EpoR activity in the kidney was associated with abnormal peritubular capillaries and tubular hypoxia, creating a “U-shaped” relationship. The direct effects of EpoR on tubular cells were confirmed in vitro by a hydrogen peroxide model using primary cultured proximal tubule cells with different EpoR activities. In summary, normal erythropoietin (EPO)/EpoR signaling in renal tubules provides defense against renal tubular injury maintains the autophagy-apoptosis balance and peritubular capillary integrity. High and low EPO/EpoR bioactivities both lead to vascular defect, and high EpoR activity overides the tubular protective effects in AKI recovery.

AB - The erythropoietin receptor (EpoR) is widely expressed but its renoprotective action is unexplored. To examine the role of EpoR in vivo in the kidney, we induced acute kidney injury (AKI) by ischemiareperfusion in mice with different EpoR bioactivities in the kidney. EpoR bioactivity was reduced by knockin of wild-type human EpoR, which is hypofunctional relative to murine EpoR, and a renal tubulespecific EpoR knockout. These mice had lower EPO/EpoR activity and lower autophagy flux in renal tubules. Upon AKI induction, they exhibited worse renal function and structural damage, more apoptosis at the acute stage (<7 days), and slower recovery with more tubulointerstitial fibrosis at the subacute stage (14 days). In contrast, mice with hyperactive EpoR signaling from knockin of a constitutively active human EpoR had higher autophagic flux, milder kidney damage, and better renal function at the acute stage but, surprisingly, worse tubulointerstitial fibrosis and renal function at the subacute stage. Either excess or deficient EpoR activity in the kidney was associated with abnormal peritubular capillaries and tubular hypoxia, creating a “U-shaped” relationship. The direct effects of EpoR on tubular cells were confirmed in vitro by a hydrogen peroxide model using primary cultured proximal tubule cells with different EpoR activities. In summary, normal erythropoietin (EPO)/EpoR signaling in renal tubules provides defense against renal tubular injury maintains the autophagy-apoptosis balance and peritubular capillary integrity. High and low EPO/EpoR bioactivities both lead to vascular defect, and high EpoR activity overides the tubular protective effects in AKI recovery.

KW - AKI

KW - Autophagy

KW - EpoR

KW - Peritubular capillary

KW - Tubulointerstitial fibrosis

UR - http://www.scopus.com/inward/record.url?scp=85045523342&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85045523342&partnerID=8YFLogxK

U2 - 10.1152/ajprenal.00306.2017

DO - 10.1152/ajprenal.00306.2017

M3 - Article

C2 - 29187371

AN - SCOPUS:85045523342

VL - 314

SP - F501-F516

JO - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

JF - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

SN - 1931-857X

IS - 4

ER -