Complement inhibition attenuates acute kidney injury after ischemia-reperfusion and limits progression to renal fibrosis in mice

Background: Renal fibrosis is a common pathophysiological feature of chronic kidney disease. Acute kidney injury (AKI) is defined as an independent causal factor of chronic kidney disease, with a pathological representation of post renal fibrosis. However, the etiopathogenesis underlying post renal fibrosis induced by AKI is not completely understood. Methods: BALB/c mice were treated with bpv or vehicle controls and were, respectively, the ischemia reperfusion (IR) model group and control group. All of the animals had blood taken from the orbital venous plexus at 24 hours after IR. Six mice in each group were randomly chosen and euthanized 7 days after IR treatment, and the remaining six mice in each group were euthanized 14 days after IR treatment. We examined the effect on post kidney fibrosis of inhibiting PTEN activity in mice in an IR induced AKI experimental model. Results: Compared with vehicle mice, bpv-(PTEN specific inhibitor) treated mice accumulated more bone marrow-derived fibroblasts and myofibroblasts in the kidneys. Inhibition of PTEN activity increased the expression of α-smooth muscle actin and extracellular matrix proteins and post kidney fibrosis. Furthermore, inhibition of PTEN activity resulted in more inflammatory cytokines in the kidneys of mice subjected to IR-induced renal fibrosis. Moreover, inhibition of PTEN activity up-regulated PI3K protein expression and Akt phosphorylation. Conclusions: Our study demonstrated that PTEN played an important role in post renal fibrosis in mice with ischemia reperfusion-induced AKI. These results indicated that the PTEN/PI3K/Akt signaling pathway may serve as a novel therapeutic target for AKI-induced chronic kidney disease.

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Mechanisms of Fasting-Mediated Protection against Renal Injury and Fibrosis Development after Ischemic Acute Kidney Injury

Biomolecules ◽

10.3390/biom9090404 ◽

2019 ◽

Vol 9 (9) ◽

pp. 404 ◽

Cited By ~ 2

Author(s):

Pedro Rojas-Morales ◽

Edilia Tapia ◽

Juan Carlos León-Contreras ◽

Susana González-Reyes ◽

Angélica Saraí Jiménez-Osorio ◽

...

Keyword(s):

Acute Kidney Injury ◽

Reperfusion Injury ◽

Renal Fibrosis ◽

Ischemia Reperfusion Injury ◽

Rat Kidney ◽

Ischemia Reperfusion ◽

Chronic Phase ◽

Kidney Injury ◽

Redox Status ◽

Extracellular Signal

Ischemia-reperfusion injury of the kidney may lead to renal fibrosis through a combination of several mechanisms. We recently demonstrated that fasting protects the rat kidney against oxidative stress and mitochondrial dysfunction in early acute kidney injury, and also against fibrosis development. Here we show that preoperative fasting preserves redox status and mitochondrial homeostasis at the chronic phase of damage after severe ischemia. Also, the protective effect of fasting coincides with the suppression of inflammation and endoplasmic reticulum stress, as well as the down-regulation of the mechanistic target of rapamycin (mTOR) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways in the fibrotic kidney. Our results demonstrate that fasting targets multiple pathophysiological mechanisms to prevent renal fibrosis and damage that results after renal ischemia-reperfusion injury.

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NFAT inhibitor 11R-VIVIT ameliorates mouse renal fibrosis after ischemia-reperfusion-induced acute kidney injury

Acta Pharmacologica Sinica ◽

10.1038/s41401-021-00833-y ◽

2021 ◽

Author(s):

Zhi-yong Xie ◽

Wei Dong ◽

Li Zhang ◽

Meng-jie Wang ◽

Zhen-meng Xiao ◽

...

Keyword(s):

Acute Kidney Injury ◽

Renal Fibrosis ◽

Nuclear Translocation ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Ckd Progression ◽

Renal Tubulointerstitial Fibrosis ◽

Underlying Mechanisms

AbstractAcute kidney injury (AKI) with maladaptive tubular repair leads to renal fibrosis and progresses to chronic kidney disease (CKD). At present, there is no curative drug to interrupt AKI-to-CKD progression. The nuclear factor of the activated T cell (NFAT) family was initially identified as a transcription factor expressed in most immune cells and involved in the transcription of cytokine genes and other genes critical for the immune response. NFAT2 is also expressed in renal tubular epithelial cells (RTECs) and podocytes and plays an important regulatory role in the kidney. In this study, we investigated the renoprotective effect of 11R-VIVIT, a peptide inhibitor of NFAT, on renal fibrosis in the AKI-to-CKD transition and the underlying mechanisms. We first examined human renal biopsy tissues and found that the expression of NFAT2 was significantly increased in RTECs in patients with severe renal fibrosis. We then established a mouse model of AKI-to-CKD transition using bilateral ischemia-reperfusion injury (Bi-IRI). The mice were treated with 11R-VIVIT (5 mg/kg, i.p.) on Days 1, 3, 10, 17 and 24 after Bi-IRI. We showed that the expression of NFAT2 was markedly increased in RTECs in the AKI-to-CKD transition. 11R-VIVIT administration significantly inhibited the nuclear translocation of NFAT2 in RTECs, decreased the levels of serum creatinine and blood urea nitrogen, and attenuated renal tubulointerstitial fibrosis but had no toxic side effects on the heart and liver. In addition, we showed that 11R-VIVIT administration alleviated RTEC apoptosis after Bi-IRI. Consistently, preapplication of 11R-VIVIT (100 nM) and transfection with NFAT2-targeted siRNA markedly suppressed TGFβ-induced HK-2 cell apoptosis in vitro. In conclusion, 11R-VIVIT administration inhibits IRI-induced NFAT2 activation and prevents AKI-to-CKD progression. Inhibiting NFAT2 may be a promising new therapeutic strategy for preventing renal fibrosis after IR-AKI.

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Ischemia Reperfusion Injury Induced Acute Kidney Injury and Subsequent Renal Fibrosis Are Attenuated By Complement Deficiency.

Transplantation Journal ◽

10.1097/00007890-201407151-01087 ◽

2014 ◽

Vol 98 ◽

pp. 337-338

Author(s):

F. Gueler ◽

A. Thorenz ◽

R. Chen ◽

S. Rong ◽

M. Jang ◽

...

Keyword(s):

Acute Kidney Injury ◽

Reperfusion Injury ◽

Renal Fibrosis ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Complement Deficiency

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Delayed Contralateral Nephrectomy Halted Post-Ischemic Renal Fibrosis Progression and Inhibited the Ischemia-Induced Fibromir Upregulation in Mice

Biomedicines ◽

10.3390/biomedicines9070815 ◽

2021 ◽

Vol 9 (7) ◽

pp. 815

Author(s):

Beáta Róka ◽

Pál Tod ◽

Tamás Kaucsár ◽

Éva Nóra Bukosza ◽

Imre Vörös ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Acute Kidney Injury ◽

Renal Fibrosis ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Target Prediction ◽

Time Points ◽

Fibrosis Progression ◽

Sham Surgery ◽

Injured Kidney

(1) Background: Ischemia reperfusion (IR) is the leading cause of acute kidney injury (AKI) and results in predisposition to chronic kidney disease. We demonstrated that delayed contralateral nephrectomy (Nx) greatly improved the function of the IR-injured kidney and decelerated fibrosis progression. Our aim was to identify microRNAs (miRNA/miR) involved in this process. (2) Methods: NMRI mice were subjected to 30 min of renal IR and one week later to Nx/sham surgery. The experiments were conducted for 7–28 days after IR. On day 8, multiplex renal miRNA profiling was performed. Expression of nine miRNAs was determined with qPCR at all time points. Based on the target prediction, plexin-A2 and Cd2AP were measured by Western blot. (3) Results: On day 8 after IR, the expression of 20/1195 miRNAs doubled, and 9/13 selected miRNAs were upregulated at all time points. Nx reduced the expression of several ischemia-induced pro-fibrotic miRNAs (fibromirs), such as miR-142a-duplex, miR-146a-5p, miR-199a-duplex, miR-214-3p and miR-223-3p, in the injured kidneys at various time points. Plexin-A2 was upregulated by IR on day 10, while Cd2AP was unchanged. (4) Conclusion: Nx delayed fibrosis progression and decreased the expression of ischemia-induced fibromirs. The protein expression of plexin-A2 and Cd2AP is mainly regulated by factors other than miRNAs.

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Cyclophilin Inhibition Protects Against Experimental Acute Kidney Injury and Renal Interstitial Fibrosis

International Journal of Molecular Sciences ◽

10.3390/ijms22010271 ◽

2020 ◽

Vol 22 (1) ◽

pp. 271

Author(s):

Khai Gene Leong ◽

Elyce Ozols ◽

John Kanellis ◽

Shawn S. Badal ◽

John T. Liles ◽

...

Keyword(s):

Acute Kidney Injury ◽

Cell Death ◽

Renal Fibrosis ◽

Ischemia Reperfusion Injury ◽

Therapeutic Potential ◽

Tissue Injury ◽

Interstitial Fibrosis ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Tubular Cell

Cyclophilins have important homeostatic roles, but following tissue injury, cyclophilin A (CypA) can promote leukocyte recruitment and inflammation, while CypD can facilitate mitochondrial-dependent cell death. This study investigated the therapeutic potential of a selective cyclophilin inhibitor (GS-642362), which does not block calcineurin function, in mouse models of tubular cell necrosis and renal fibrosis. Mice underwent bilateral renal ischemia/reperfusion injury (IRI) and were killed 24 h later: treatment with 10 or 30 mg/kg/BID GS-642362 (or vehicle) began 1 h before surgery. In the second model, mice underwent unilateral ureteric obstruction (UUO) surgery and were killed 7 days later; treatment with 10 or 30 mg/kg/BID GS-642362 (or vehicle) began 1 h before surgery. GS-642362 treatment gave a profound and dose-dependent protection from acute renal failure in the IRI model. This protection was associated with reduced tubular cell death, including a dramatic reduction in neutrophil infiltration. In the UUO model, GS-642362 treatment significantly reduced tubular cell death, macrophage infiltration, and renal fibrosis. This protective effect was independent of the upregulation of IL-2 and activation of the stress-activated protein kinases (p38 and JNK). In conclusion, GS-642362 was effective in suppressing both acute kidney injury and renal fibrosis. These findings support further investigation of cyclophilin blockade in other types of acute and chronic kidney disease.

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Post-treatment with JP-1302 protects against renal ischemia/reperfusion-induced acute kidney injury in rats

Journal of Pharmacological Sciences ◽

10.1016/j.jphs.2018.12.008 ◽

2019 ◽

Vol 139 (3) ◽

pp. 137-142 ◽

Cited By ~ 5

Author(s):

Takaomi Shimokawa ◽

Hidenobu Tsutsui ◽

Takeshi Miura ◽

Masashi Takama ◽

Kohei Hayashi ◽

...

Keyword(s):

Acute Kidney Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Post Treatment ◽

Renal Ischemia

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Hydrogen sulfide reduces pyroptosis and alleviates ischemia-reperfusion acute kidney injury by inhibiting NLRP3 inflammasome

Life Sciences ◽

10.1016/j.lfs.2021.119466 ◽

2021 ◽

pp. 119466

Author(s):

Jindi Ni ◽

Lijing Jiang ◽

Guofeng Shen ◽

Zhuye Xia ◽

Lu Zhang ◽

...

Keyword(s):

Acute Kidney Injury ◽

Hydrogen Sulfide ◽

Nlrp3 Inflammasome ◽

Ischemia Reperfusion ◽

Kidney Injury

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Characterization of urinary exosomal release of aquaporin-1 and -2 after renal ischemia-reperfusion in rats

AJP Renal Physiology ◽

10.1152/ajprenal.00184.2017 ◽

2018 ◽

Vol 314 (4) ◽

pp. F584-F601 ◽

Cited By ~ 21

Author(s):

Siree Asvapromtada ◽

Hiroko Sonoda ◽

Minami Kinouchi ◽

Sayaka Oshikawa ◽

Saki Takahashi ◽

...

Keyword(s):

Renal Fibrosis ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Interacting Protein ◽

Aquaporin 1 ◽

Water Handling ◽

Marker Proteins ◽

Apical Trafficking ◽

Renal Expression

Acute kidney injury (AKI) is an important risk factor for the development of chronic kidney disease (CKD), and an alteration in renal water handling has been observed during the transition of AKI to CKD. Urinary exosomal release of aquaporin-1 (AQP1) and AQP2, important proteins for renal water handling, has recently been reported to predict their levels of renal expression. Therefore, we examined the patterns of urinary exosomal release of AQP1 and AQP2, and the exosomal marker proteins tumor susceptibility 101 protein (TSG101) and ALG-2 interacting protein X (Alix), in the acute and chronic phases following induction of AKI by renal bilateral ischemia/reperfusion (I/R) in rats. Blood tests and histological examinations indicated that AKI occurred before at 7 days after renal I/R ( day 7) and that renal fibrosis developed progressively thereafter. Immunoblotting demonstrated significant decreases in the urinary exosomal release of AQP1 and AQP2 during severe AKI. Urinary exosomal release of Alix and TSG101 was significantly increased on day 7. These data were also confirmed in rats with unilateral renal I/R causing more serious AKI. Urinary exosomal release of either the Ser-256- or Ser-269-phosphorylated form of AQP2, both of which are involved in apical trafficking of AQP2, was positively correlated with that of total AQP2. These results suggest that urinary exosomal release of AQP1 and AQP2 is reduced in I/R-induced AKI, whereas that of Alix and TSG101 is increased in the initial phase of renal fibrosis. Furthermore, apical trafficking of AQP2 appears to be related to urinary exosomal release of AQP2.

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