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Telomerase deficiency delays renal recovery in mice after ischemia-reperfusion injury by impairing autophagy.

ABSTRACT: The aged population suffers increased morbidity and higher mortality in response to episodes of acute kidney injury (AKI). Aging is associated with telomere shortening, and both telomerase reverse transcriptase (TerT) and RNA (TerC) are essential to maintain telomere length. To define a role of telomerase deficiency in susceptibility to AKI, we used ischemia/reperfusion injury in wild-type mice or mice with either TerC or TerT deletion. Injury induced similar renal impairment at day 1 in each genotype, as assessed by azotemia, proteinuria, acute tubular injury score, and apoptotic tubular epithelial cell index. However, either TerC or TerT knockout significantly delayed recovery compared with wild-type mice. Electron microscopy showed increased autophagosome formation in renal tubular epithelial cells in wild-type mice but a significant delay of their development in TerC and TerT knockout mice. There were also impeded increases in the expression of the autophagosome marker LC3 II, prolonged accumulation of the autophagosome protein P62, an increase of the cell cycle regulator p16, and greater activation of the mammalian target of rapamycin (mTOR) pathway. The mTORC1 inhibitor, rapamycin, partially restored the ischemia/reperfusion-induced autophagy response, without a significant effect on either p16 induction or tubule epithelial cell proliferation. Thus, muting the maintenance of normal telomere length in mice impaired recovery from AKI, owing to an increase in tubule cell senescence and impairment of mTOR-mediated autophagy.

SUBMITTER: Cheng H

PROVIDER: S-EPMC4490111 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Telomerase deficiency delays renal recovery in mice after ischemia-reperfusion injury by impairing autophagy.

Cheng Huifang H Fan Xiaofeng X Lawson William E WE Paueksakon Paisit P Harris Raymond C RC

Kidney international 20150311 1

The aged population suffers increased morbidity and higher mortality in response to episodes of acute kidney injury (AKI). Aging is associated with telomere shortening, and both telomerase reverse transcriptase (TerT) and RNA (TerC) are essential to maintain telomere length. To define a role of telomerase deficiency in susceptibility to AKI, we used ischemia/reperfusion injury in wild-type mice or mice with either TerC or TerT deletion. Injury induced similar renal impairment at day 1 in each ge ...[more]

PMID: 25760322

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Project description:Introduction: Elevated levels of mitochondrial reactive oxygen species (ROS) contribute to the development of numerous cardiovascular diseases. TERT, the catalytic subunit of telomerase, has been shown to translocate to mitochondria to suppress ROS while promoting ATP production. Acute overexpression of TERT increases survival and decreases infarct size in a mouse model of myocardial infarct, while decreased telomerase activity predisposes to mitochondrial defects and heart failure. In the present study, we examined the role of TERT on cardiac structure and function under basal conditions and conditions of acute or prolonged stress in a novel rat model of TERT deficiency. Methods: Cardiac structure and function were evaluated via transthoracic echocardiogram. Langendorff preparations were used to test the effects of acute global ischemia reperfusion injury on cardiac function and infarction. Coronary flow and left ventricular pressure were measured during and after ischemia/reperfusion (I/R). Mitochondrial DNA integrity was measured by PCR and mitochondrial respiration was assessed in isolated mitochondria using an Oxygraph. Angiotensin II infusion was used as an established model of systemic stress. Results: No structural changes (echocardiogram) or coronary flow/left ventricle pressure (isolated hearts) were observed in TERT-/- rats at baseline; however, after I/R, coronary flow was significantly reduced in TERT-/- compared to wild type (WT) rats, while diastolic Left Ventricle Pressure was significantly elevated (n = 6 in each group; p < 0.05) in the TERT-/-. Interestingly, infarct size was less in TERT-/- rats compared to WT rats, while mitochondrial respiratory control index decreased and mitochondrial DNA lesions increased in TERT-/- compared to WT. Angiotensin II treatment did not alter cardiac structure or function; however, it augmented the infarct size significantly more in TERT-/- compared to the WT. Conclusion: Absence of TERT activity increases susceptibility to stress like cardiac injury. These results suggest a critical role of telomerase in chronic heart disease.

Project description:BackgroundAcute renal injury (AKI) secondary to ischemia reperfusion (IR) injury continues to be a significant perioperative problem and there is no effective treatment. Mindin belongs to the mindin/F-spondin family and involves in inflammation, proliferation, and cell apoptosis. Previous studies have explored the biological functions of mindin in liver and brain ischemic injury, but its role in AKI is unknown.MethodTo investigate whether mindin has a pathogenic role, mindin knockout (KO) and wild-type (WT) mice were used to establish renal IR model. After 30 min of ischemia and 24 h of reperfusion, renal histology, serum creatinine, and inflammatory response were examined to assess kidney injury. In vitro, proinflammatory factors and inflammatory signaling pathways were measured in mindin overexpression or knockdown and vector cells after hypoxia/reoxygenation (HR).ResultsFollowing IR, the kidney mindin level was increased in WT mice and deletion of mindin provided significant protection for mice against IR-induced renal injury as manifested by attenuated the elevation of serum creatinine and blood urea nitrogen along with less severity for histological alterations. Mindin deficiency significantly suppressed inflammatory cell infiltration, TNF-α and MCP-1 production following renal IR injury. Mechanistic studies revealed that mindin deficiency inhibits TLR4/JNK/NF-κB signaling activation. In vitro, the expression levels of TNF-α and MCP-1 were increased in mindin overexpression cells compared with vector cells following HR. Moreover, TLR4/JNK/NF-κB signaling activation was elevated in the mindin overexpression cells in response to HR stimulation while mindin knockdown inhibited the activation of TLR4/JNK/ NF-κB signaling after HR in vitro. Further study showed that mindin protein interacted directly with TLR4 protein. And more, mindin protein was confirmed to be expressed massively in renal tubule tissues of human hydronephrosis patients.ConclusionThese data demonstrate that mindin is a critical modulator of renal IR injury through regulating inflammatory responses. TLR4/JNK/NF-κB signaling most likely mediates the biological function of mindin in this model of renal ischemia.

Project description:Penehyclidine hydrochloride (PHC) suppresses renal ischemia and reperfusion (I/R) injury (IRI); however, the underlying mechanism of action that achieves this function remains largely unknown. The present study aimed to investigate the potential role of autophagy in PHC?induced suppression of renal IRI, as well as the involvement of cell proliferation and apoptosis. A rat IRI model and a cellular hypoxia/oxygenation (H/R) model were established; PHC, 3?methyladenine (3?MA) and rapamycin (Rapa) were administered to the IRI model rats prior to I/R induction and to H/R cells following reperfusion. Serum creatinine was measured using a biochemistry analyzer, whereas aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) expression levels were detected using ELISA kits. Renal tissue injury was evaluated by histological examination. In addition, microtubule?associated protein light chain 3B (LC3B) expression, autophagosome formation, cell proliferation and apoptosis were detected in the cellular H/R model. The results demonstrated that I/R induced renal injury in IRI model rats, upregulated serum creatinine, ALAT and ASAT expression levels, and increased autophagic processes. In contrast, pretreatment with PHC or Rapa significantly prevented these I/R?induced changes, whereas the administration of 3?MA enhanced I/R?induced injuries through suppressing autophagy. PHC and Rapa increased LC3B and Beclin?1 expression levels, but decreased sequestome 1 (p62) expression in the cellular H/R model, whereas 3?MA prevented these PHC?induced changes. PHC and Rapa promoted proliferation and autophagy in the cellular H/R model; these effects were accompanied by increased expression levels of LC3B and Beclin?1, and reduced p62 expression levels, whereas these levels were inhibited by 3?MA. Furthermore, PHC and Rapa inhibited apoptosis in the cellular H/R model through increasing Bcl?2 expression levels, and suppressing Bax and caspase?3 expression levels; the opposite effect was induced by 3?MA. In conclusion, PHC suppressed renal IRI through the induction of autophagy, which in turn promoted proliferation and suppressed apoptosis in renal cells.

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Telomerase deficiency delays renal recovery in mice after ischemia-reperfusion injury by impairing autophagy.

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Telomerase deficiency delays renal recovery in mice after ischemia-reperfusion injury by impairing autophagy.

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