PKC-δ promotes renal tubular cell apoptosis associated with proteinuria

Xiaoning Li, Navjotsingh Pabla, Qingqing Wei, Guie Dong, Robert O. Messing, Cong Yi Wang, Zheng Dong

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Proteinuria may contribute to progressive renal damage by inducing tubulointerstitial inflammation, fibrosis, and tubular cell injury and death, but the mechanisms underlying these pathologic changes remain largely unknown. Here, in a rat kidney proximal tubular cell line (RPTC), albumin induced apoptosis in a time- and dose-dependent manner. Caspase activation accompanied albumin-induced apoptosis, and general caspase inhibitors could suppress this activation. In addition, Bcl-2 transfection inhibited apoptosis and attenuated albumin-induced Bax translocation to mitochondria and cytochrome c release from the organelles, further confirming a role for the intrinsic pathway of apoptosis in albuminuria-associated tubular apoptosis. We observed phosphorylation and activation of PKC-δ early during treatment of RPTC cells with albumin. Rottlerin, a pharmacologic inhibitor of PKC-δ, suppressed albumin-induced Bax translocation, cytochrome c release, and apoptosis. Moreover, a dominant-negative mutant of PKC-δ blocked albumin-induced apoptosis in RPTC cells. In vivo, we observed activated PKC-δ in proteinuric kidneys of streptozotocin-induced diabetic mice and in kidneys after direct albumin overload. Notably, albumin overload induced apoptosis in renal tubules, which was less severe in PKC-δ-knockout mice. Taken together, these results suggest that activation of PKC-δ promotes tubular cell injury and death during albuminuria, broadening our understanding of the pathogenesis of progressive proteinuric kidney diseases.

Original languageEnglish (US)
Pages (from-to)1115-1124
Number of pages10
JournalJournal of the American Society of Nephrology
Volume21
Issue number7
DOIs
StatePublished - Jul 1 2010

Fingerprint

Proteinuria
Albumins
Apoptosis
Kidney
Albuminuria
Cytochromes c
Cell Line
Cell Death
Caspase Inhibitors
Wounds and Injuries
Kidney Diseases
Streptozocin
Caspases
Knockout Mice
Organelles
Transfection
Mitochondria
Fibrosis
Phosphorylation
Inflammation

ASJC Scopus subject areas

  • Nephrology

Cite this

PKC-δ promotes renal tubular cell apoptosis associated with proteinuria. / Li, Xiaoning; Pabla, Navjotsingh; Wei, Qingqing; Dong, Guie; Messing, Robert O.; Wang, Cong Yi; Dong, Zheng.

In: Journal of the American Society of Nephrology, Vol. 21, No. 7, 01.07.2010, p. 1115-1124.

Research output: Contribution to journalArticle

Li, Xiaoning ; Pabla, Navjotsingh ; Wei, Qingqing ; Dong, Guie ; Messing, Robert O. ; Wang, Cong Yi ; Dong, Zheng. / PKC-δ promotes renal tubular cell apoptosis associated with proteinuria. In: Journal of the American Society of Nephrology. 2010 ; Vol. 21, No. 7. pp. 1115-1124.
@article{7f85f7b156f94d288036b2a42ff58693,
title = "PKC-δ promotes renal tubular cell apoptosis associated with proteinuria",
abstract = "Proteinuria may contribute to progressive renal damage by inducing tubulointerstitial inflammation, fibrosis, and tubular cell injury and death, but the mechanisms underlying these pathologic changes remain largely unknown. Here, in a rat kidney proximal tubular cell line (RPTC), albumin induced apoptosis in a time- and dose-dependent manner. Caspase activation accompanied albumin-induced apoptosis, and general caspase inhibitors could suppress this activation. In addition, Bcl-2 transfection inhibited apoptosis and attenuated albumin-induced Bax translocation to mitochondria and cytochrome c release from the organelles, further confirming a role for the intrinsic pathway of apoptosis in albuminuria-associated tubular apoptosis. We observed phosphorylation and activation of PKC-δ early during treatment of RPTC cells with albumin. Rottlerin, a pharmacologic inhibitor of PKC-δ, suppressed albumin-induced Bax translocation, cytochrome c release, and apoptosis. Moreover, a dominant-negative mutant of PKC-δ blocked albumin-induced apoptosis in RPTC cells. In vivo, we observed activated PKC-δ in proteinuric kidneys of streptozotocin-induced diabetic mice and in kidneys after direct albumin overload. Notably, albumin overload induced apoptosis in renal tubules, which was less severe in PKC-δ-knockout mice. Taken together, these results suggest that activation of PKC-δ promotes tubular cell injury and death during albuminuria, broadening our understanding of the pathogenesis of progressive proteinuric kidney diseases.",
author = "Xiaoning Li and Navjotsingh Pabla and Qingqing Wei and Guie Dong and Messing, {Robert O.} and Wang, {Cong Yi} and Zheng Dong",
year = "2010",
month = "7",
day = "1",
doi = "10.1681/ASN.2009070760",
language = "English (US)",
volume = "21",
pages = "1115--1124",
journal = "Journal of the American Society of Nephrology : JASN",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "7",

}

TY - JOUR

T1 - PKC-δ promotes renal tubular cell apoptosis associated with proteinuria

AU - Li, Xiaoning

AU - Pabla, Navjotsingh

AU - Wei, Qingqing

AU - Dong, Guie

AU - Messing, Robert O.

AU - Wang, Cong Yi

AU - Dong, Zheng

PY - 2010/7/1

Y1 - 2010/7/1

N2 - Proteinuria may contribute to progressive renal damage by inducing tubulointerstitial inflammation, fibrosis, and tubular cell injury and death, but the mechanisms underlying these pathologic changes remain largely unknown. Here, in a rat kidney proximal tubular cell line (RPTC), albumin induced apoptosis in a time- and dose-dependent manner. Caspase activation accompanied albumin-induced apoptosis, and general caspase inhibitors could suppress this activation. In addition, Bcl-2 transfection inhibited apoptosis and attenuated albumin-induced Bax translocation to mitochondria and cytochrome c release from the organelles, further confirming a role for the intrinsic pathway of apoptosis in albuminuria-associated tubular apoptosis. We observed phosphorylation and activation of PKC-δ early during treatment of RPTC cells with albumin. Rottlerin, a pharmacologic inhibitor of PKC-δ, suppressed albumin-induced Bax translocation, cytochrome c release, and apoptosis. Moreover, a dominant-negative mutant of PKC-δ blocked albumin-induced apoptosis in RPTC cells. In vivo, we observed activated PKC-δ in proteinuric kidneys of streptozotocin-induced diabetic mice and in kidneys after direct albumin overload. Notably, albumin overload induced apoptosis in renal tubules, which was less severe in PKC-δ-knockout mice. Taken together, these results suggest that activation of PKC-δ promotes tubular cell injury and death during albuminuria, broadening our understanding of the pathogenesis of progressive proteinuric kidney diseases.

AB - Proteinuria may contribute to progressive renal damage by inducing tubulointerstitial inflammation, fibrosis, and tubular cell injury and death, but the mechanisms underlying these pathologic changes remain largely unknown. Here, in a rat kidney proximal tubular cell line (RPTC), albumin induced apoptosis in a time- and dose-dependent manner. Caspase activation accompanied albumin-induced apoptosis, and general caspase inhibitors could suppress this activation. In addition, Bcl-2 transfection inhibited apoptosis and attenuated albumin-induced Bax translocation to mitochondria and cytochrome c release from the organelles, further confirming a role for the intrinsic pathway of apoptosis in albuminuria-associated tubular apoptosis. We observed phosphorylation and activation of PKC-δ early during treatment of RPTC cells with albumin. Rottlerin, a pharmacologic inhibitor of PKC-δ, suppressed albumin-induced Bax translocation, cytochrome c release, and apoptosis. Moreover, a dominant-negative mutant of PKC-δ blocked albumin-induced apoptosis in RPTC cells. In vivo, we observed activated PKC-δ in proteinuric kidneys of streptozotocin-induced diabetic mice and in kidneys after direct albumin overload. Notably, albumin overload induced apoptosis in renal tubules, which was less severe in PKC-δ-knockout mice. Taken together, these results suggest that activation of PKC-δ promotes tubular cell injury and death during albuminuria, broadening our understanding of the pathogenesis of progressive proteinuric kidney diseases.

UR - http://www.scopus.com/inward/record.url?scp=77954587516&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954587516&partnerID=8YFLogxK

U2 - 10.1681/ASN.2009070760

DO - 10.1681/ASN.2009070760

M3 - Article

C2 - 20395372

AN - SCOPUS:77954587516

VL - 21

SP - 1115

EP - 1124

JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

SN - 1046-6673

IS - 7

ER -