Abstract
Background Necroptosis is a newly discovered cell death pathway that plays a critical role in AKI. The involvement of integrin-linked kinase (ILK) in necroptosis has not been studied. Methods We performed experiments in mice with an Ilk deletion in collecting duct (CD) principal cells (PCs), and cultured tubular epithelial cells treated with an ILK inhibitor or ILK siRNA knockdown. Results Ilk deletion in CD PCs resulted in acute tubular injury and early mortality in mice. Progressive interstitial fibrosis and inflammation associated with the activation of the canonical TGF-b signaling cascade were detected in the kidneys of the mice lacking ILK in the CD PCs. In contrast to the minimal apoptosis detected in the animals' injured CDs, widespread necroptosis was present in ILK-deficient PCs, characterized by cell swelling, deformed mitochondria, and rupture of plasmamembrane. In addition, ILK deficiency resulted in increased expression and activation of necroptotic proteins MLKL and RIPK3, andmembrane translocation ofMLKL in CD PCs. ILK inhibition and siRNA knockdown reduced cell survival in cultured tubular cells, concomitant with increased membrane accumulation of MLKL and/or phospho-MLKL. Administration of a necroptosis inhibitor, necrostatin-1, blocked cell death in vitro and significantly attenuated inflammation, interstitial fibrosis, and renal failure in ILK-deficient mice. Conclusions The study demonstrates the critical involvement of ILK in necroptosis through modulation of the RIPK3 and MLKL pathway and highlights the contribution of CD PC injury to the development of inflammation and interstitial fibrosis of the kidney.
| Original language | English |
|---|---|
| Pages (from-to) | 2073-2090 |
| Number of pages | 18 |
| Journal | Journal of the American Society of Nephrology |
| Volume | 30 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Jan 1 2019 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Nephrology
Cite this
Integrin-linked kinase deficiency in collecting duct principal cell promotes necroptosis of principal cell and contributes to kidney inflammation and fibrosis. / Huang, Ming; Zhu, Shuai; Huang, Huihui; He, Jinzhao; Tsuji, Kenji; Jin, William W.; Xie, Dongping; Ham, Onju; Capen, Diane E.; Lu, Weining; Paunescu, Teodor G.; Yang, Baoxue; Lu, Hua A.Jenny.
In: Journal of the American Society of Nephrology, Vol. 30, No. 11, 01.01.2019, p. 2073-2090.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Integrin-linked kinase deficiency in collecting duct principal cell promotes necroptosis of principal cell and contributes to kidney inflammation and fibrosis
AU - Huang, Ming
AU - Zhu, Shuai
AU - Huang, Huihui
AU - He, Jinzhao
AU - Tsuji, Kenji
AU - Jin, William W.
AU - Xie, Dongping
AU - Ham, Onju
AU - Capen, Diane E.
AU - Lu, Weining
AU - Paunescu, Teodor G.
AU - Yang, Baoxue
AU - Lu, Hua A.Jenny
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Background Necroptosis is a newly discovered cell death pathway that plays a critical role in AKI. The involvement of integrin-linked kinase (ILK) in necroptosis has not been studied. Methods We performed experiments in mice with an Ilk deletion in collecting duct (CD) principal cells (PCs), and cultured tubular epithelial cells treated with an ILK inhibitor or ILK siRNA knockdown. Results Ilk deletion in CD PCs resulted in acute tubular injury and early mortality in mice. Progressive interstitial fibrosis and inflammation associated with the activation of the canonical TGF-b signaling cascade were detected in the kidneys of the mice lacking ILK in the CD PCs. In contrast to the minimal apoptosis detected in the animals' injured CDs, widespread necroptosis was present in ILK-deficient PCs, characterized by cell swelling, deformed mitochondria, and rupture of plasmamembrane. In addition, ILK deficiency resulted in increased expression and activation of necroptotic proteins MLKL and RIPK3, andmembrane translocation ofMLKL in CD PCs. ILK inhibition and siRNA knockdown reduced cell survival in cultured tubular cells, concomitant with increased membrane accumulation of MLKL and/or phospho-MLKL. Administration of a necroptosis inhibitor, necrostatin-1, blocked cell death in vitro and significantly attenuated inflammation, interstitial fibrosis, and renal failure in ILK-deficient mice. Conclusions The study demonstrates the critical involvement of ILK in necroptosis through modulation of the RIPK3 and MLKL pathway and highlights the contribution of CD PC injury to the development of inflammation and interstitial fibrosis of the kidney.
AB - Background Necroptosis is a newly discovered cell death pathway that plays a critical role in AKI. The involvement of integrin-linked kinase (ILK) in necroptosis has not been studied. Methods We performed experiments in mice with an Ilk deletion in collecting duct (CD) principal cells (PCs), and cultured tubular epithelial cells treated with an ILK inhibitor or ILK siRNA knockdown. Results Ilk deletion in CD PCs resulted in acute tubular injury and early mortality in mice. Progressive interstitial fibrosis and inflammation associated with the activation of the canonical TGF-b signaling cascade were detected in the kidneys of the mice lacking ILK in the CD PCs. In contrast to the minimal apoptosis detected in the animals' injured CDs, widespread necroptosis was present in ILK-deficient PCs, characterized by cell swelling, deformed mitochondria, and rupture of plasmamembrane. In addition, ILK deficiency resulted in increased expression and activation of necroptotic proteins MLKL and RIPK3, andmembrane translocation ofMLKL in CD PCs. ILK inhibition and siRNA knockdown reduced cell survival in cultured tubular cells, concomitant with increased membrane accumulation of MLKL and/or phospho-MLKL. Administration of a necroptosis inhibitor, necrostatin-1, blocked cell death in vitro and significantly attenuated inflammation, interstitial fibrosis, and renal failure in ILK-deficient mice. Conclusions The study demonstrates the critical involvement of ILK in necroptosis through modulation of the RIPK3 and MLKL pathway and highlights the contribution of CD PC injury to the development of inflammation and interstitial fibrosis of the kidney.
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U2 - 10.1681/ASN.2018111162
DO - 10.1681/ASN.2018111162
M3 - Article
C2 - 31653783
AN - SCOPUS:85074378581
VL - 30
SP - 2073
EP - 2090
JO - Journal of the American Society of Nephrology : JASN
JF - Journal of the American Society of Nephrology : JASN
SN - 1046-6673
IS - 11
ER -