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PARP-1 inhibits glycolysis in ischemic kidneys.

ABSTRACT: After ischemic renal injury (IRI), selective damage occurs in the S(3) segments of the proximal tubules as a result of inhibition of glycolysis, but the mechanism of this inhibition is unknown. We previously reported that inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) activity protects against ischemia-induced necrosis in proximal tubules by preserving ATP levels. Here, we tested whether PARP-1 activation in proximal tubules after IRI leads to poly(ADP-ribosyl)ation of the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a modification that inhibits its activity. Using in vitro and in vivo models, under hypoxic conditions, we detected poly(ADP-ribosyl)ation and reduced activity of GAPDH; inhibition of PARP-1 activity restored GAPDH activity and ATP levels. Inhibition of GAPDH with iodoacetate exacerbated ATP depletion, cytotoxicity, and necrotic cell death of LLCPK(1) cells subjected to hypoxic conditions, whereas inhibition of PARP-1 activity was cytoprotective. In conclusion, these data indicate that poly(ADP-ribosyl)ation of GAPDH and the subsequent inhibition of anaerobic respiration exacerbate ATP depletion selectively in the proximal tubule after IRI.

SUBMITTER: Devalaraja-Narashimha K

PROVIDER: S-EPMC2615730 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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PARP-1 inhibits glycolysis in ischemic kidneys.

Devalaraja-Narashimha Kishor K Padanilam Babu J BJ

Journal of the American Society of Nephrology : JASN 20081203 1

After ischemic renal injury (IRI), selective damage occurs in the S(3) segments of the proximal tubules as a result of inhibition of glycolysis, but the mechanism of this inhibition is unknown. We previously reported that inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) activity protects against ischemia-induced necrosis in proximal tubules by preserving ATP levels. Here, we tested whether PARP-1 activation in proximal tubules after IRI leads to poly(ADP-ribosyl)ation of the key glycolytic e ...[more]

PMID: 19056868

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Project description:Purpose: Angiogenesis post-ischemia plays an essential role in preventing ischemic damage to tissue by improving the blood recovery. Determining the regulatory mechanism of ischemic angiogenesis, therefore, could provide effective therapeutics for ischemic injury. Materials and Methods: The RNA sequencing (RNA-seq) database was used to predict the association of gamma-aminobutyric acid type B receptor subunit 2 (GABBR2) with endothelial-specific expression. The role of GABBR2 in angiogenesis was verified in vitro by downregulating GABBR2 in human umbilical vein endothelial cells (HUVECs) with lentiviral vectors. Besides, the in vivo effect of GABBR2 on the blood recovery of an ischemic hindlimb was demonstrated by establishing a hindlimb ischemia model in normal and GABBR2 adenoviral vector-infected mice. Then, the mobilization of endothelial progenitor cells (EPCs) in peripheral blood post-ischemia was determined by flow cytometry. Finally, the XF analyzer and Western blot were used to determine the effect of GABBR2 on endothelial metabolism. Results: The RNA-seq results indicated a strong association between GABBR2 and endothelial revascularization, and the upregulation of GABBR2 was detected in both hypoxia-treated HUVECs and ischemic mouse hindlimb. Hypoxia treatment for 6 h increased the proliferation, migration, and tube formation of HUVECs, which were inhibited by GABBR2 knockdown. Additionally, GABBR2 downregulation significantly decreased the blood flow recovery of mouse ischemic hindlimb. The expressions of the EPC markers CD34+ and CD133+ significantly decreased in the peripheral blood in hindlimb post-ischemia. Mechanically, glycolysis-dominated metabolism of HUVECs was compromised by GABBR2 knockdown. Evidences of the decreased expressions of HKII, PFKFB3, and PKM1 also supported the compromised glycolysis induced by GABBR2 downregulation. Conclusion: Our study demonstrated that GABBR2 regulated angiogenesis post-ischemia by inhibiting the glycolysis pathway.

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PARP-1 inhibits glycolysis in ischemic kidneys.

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PARP-1 inhibits glycolysis in ischemic kidneys.

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