Role of Atrophic Tubules in Development of Interstitial Fibrosis in Microembolism-Induced Renal Failure in Rat

Suzuki, Takayuki; Kimura, Masato; Asano, Mitsuko; Fujigaki, Yoshihide; Hishida, Akira

doi:10.1016/s0002-9440(10)63946-6

Cited by 51 publications

(42 citation statements)

References 39 publications

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“…Therefore, the beneficial effects of TGF-b activation and ECM synthesis are transient. Suzuki et al 59 also reported that tubular injury led to the development of surrounding matrix protein deposition and contributed to the pathogenesis of interstitial fibrosis. Indeed, Fujigaki et al 58 used a single intravenous injection of uranyl acetate (5 mg/kg) into Sprague-Dawley rats; tubular injury reached its peak 7 days after the injection, and then, tubules underwent a repair and regeneration process.…”

Section: Discussionmentioning

confidence: 99%

Autophagy Regulates TGF-β Expression and Suppresses Kidney Fibrosis Induced by Unilateral Ureteral Obstruction

Ding

Kim

Lee

et al. 2014

Journal of the American Society of Nephrology

223

200

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Autophagy is an evolutionarily conserved process that cells use to degrade and recycle cellular proteins and remove damaged organelles. During the past decade, there has been a growing interest in defining the basic cellular mechanism of autophagy and its roles in health and disease. However, the functional role of autophagy in kidney fibrosis remains poorly understood. Here, using GFP-LC3 transgenic mice, we show that autophagy is induced in renal tubular epithelial cells (RTECs) of obstructed kidneys after unilateral ureteral obstruction (UUO). Deletion of LC3B (LC3 2/2 mice) resulted in increased collagen deposition and increased mature profibrotic factor TGF-b levels in obstructed kidneys. Beclin 1 heterozygous (beclin 1 +/2 ) mice also displayed increased collagen deposition in the obstructed kidneys after UUO. We also show that TGF-b1 induces autophagy in primary mouse RTECs and human renal proximal tubular epithelial (HK-2) cells. LC3 deficiency resulted in increased levels of mature TGF-b in primary RTECs. Under conditions of TGF-b1 stimulation and autoinduction, inhibition of autolysosomal protein degradation by bafilomycin A1 increased mature TGF-b protein levels without alterations in TGF-b1 mRNA. These data suggest a novel intracellular mechanism by which mature TGF-b1 protein levels may be regulated in RTECs through autophagic degradation, which suppresses kidney fibrosis induced by UUO. The dual functions of TGF-b1, as an inducer of TGF-b1 autoinduction and an inducer of autophagy and TGF-b degradation, underscore the multifunctionality of TGF-b1.

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Section: Discussionmentioning

confidence: 99%

Autophagy Regulates TGF-β Expression and Suppresses Kidney Fibrosis Induced by Unilateral Ureteral Obstruction

Ding

Kim

Lee

et al. 2014

Journal of the American Society of Nephrology

223

200

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“…31 Therefore, vimentin expression in tubules late after injury (when recovery should be complete) indicates defective repair with abnormally dedifferentiated epithelium. 26,27,31,33 Accordingly, 7 days post-I/R, tubules expressed vimentin in proportion to necrosis at 3 days ( Figure 4A), with sharp transitions between epithelium without and with vimentin (Supplemental Figure 2A). As expected, 3/4 NX sham I/R kidneys showed staining only in glomeruli and interstitial fibroblasts.…”

Section: Rmr By 3/4 Nx Delays Functional Recovery Andmentioning

confidence: 95%

“…9,[23][24][25][26][27][28][29] To investigate whether RMR deters regenerating proximal tubules (PTs) from differentiating during recovery from I/R, we performed immunohistochemistry (IHC) for vimentin. Absent in normal PTs, vimentin becomes expressed when surviving cells dedifferentiate and proliferate after AKI.…”

Section: Rmr By 3/4 Nx Delays Functional Recovery Andmentioning

confidence: 99%

Severe Renal Mass Reduction Impairs Recovery and Promotes Fibrosis after AKI

Polichnowski¹,

Lan

Geng

et al. 2014

Journal of the American Society of Nephrology

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Preexisting CKD may affect the severity of and/or recovery from AKI. We assessed the impact of prior graded normotensive renal mass reduction on ischemia-reperfusion-induced AKI. Rats underwent 40 minutes of ischemia 2 weeks after right uninephrectomy and surgical excision of both poles of the left kidney (75% reduction of renal mass), right uninephrectomy (50% reduction of renal mass), or sham reduction of renal mass. The severity of AKI was comparable among groups, which was reflected by similarly increased serum creatinine (S Cr ; approximately 4.5 mg/dl) at 2 days, tubule necrosis at 3 days, and vimentinexpressing regenerating tubules at 7 days postischemia-reperfusion. However, S Cr remained elevated compared with preischemia-reperfusion values, and more tubules failed to differentiate during late recovery 4 weeks after ischemia-reperfusion in rats with 75% renal mass reduction relative to other groups. Tubules that failed to differentiate continued to produce vimentin, exhibited vicarious proliferative signaling, and expressed less vascular endothelial growth factor but more profibrotic peptides. The disproportionate failure of regenerating tubules to redifferentiate in rats with 75% renal mass reduction associated with more severe capillary rarefaction and greater tubulointerstitial fibrosis. Furthermore, initially normotensive rats with 75% renal mass reduction developed hypertension and proteinuria, 2-4 weeks postischemia-reperfusion. In summary, severe (.50%) renal mass reduction disproportionately compromised tubule repair, diminished capillary density, and promoted fibrosis with hypertension after ischemia-reperfusion-induced AKI in rats, suggesting that accelerated declines of renal function may occur after AKI in patients with preexisting CKD. 25: 149625: -150725: , 201425: . doi: 10.1681 Clinical studies suggest that AKI worsens preexisting CKD and accelerates progression to end stage because of residual structural and functional deficits. 1-7 CKD, per se, may increase the risk and severity of AKI and the likelihood of incomplete recovery from AKI. 8 Thus, AKI and CKD reinforce each other to increase nephron loss and tubulointerstitial fibrosis (TIF). 9 Nevertheless, causal relationships for both aspects of the AKI-CKD nexus 10 (AKI resulting in CKD/ESRD and CKD, per se, predisposing to AKI) have been questioned. 11,12 These concerns were recently reviewed. 13 AKI-CKD relationships have also been questioned on the grounds that mechanisms for AKI-CKD interactions are ill-defined and controversial. [14][15][16] We addressed these uncertainties by investigating the impact of normotensive renal mass reduction (RMR; 0%, 50%, and 75%) of 2-weeks duration on AKI induced by ischemia-reperfusion (I/R) in rats. We addressed three questions. (1) Does prior RMR increase AKI severity? (2) Does prior RMR impair recovery from AKI? (3) Does prior RMR predispose to the development of more severe TIF during J Am Soc Nephrol

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“…Because PTEN-deficient tubules failed to recover normal structure after AKI, we surmised that they would express vimentin, a marker for dedifferentiation in regenerating PT, that becomes suppressed again as tubules redifferentiate (15,39,43,44). Atrophic tubules in chronic kidney disease (CKD) also express vimentin (15).…”

Section: Animalsmentioning

confidence: 99%

“…Tubule defects that cause TIF after AKI include increased activity of transforming growth factor (TGF)-␤ (14, 37), Notch (3), c-Jun N-terminal kinase (JNK) (10,17,27,45), plateletderived growth factor (PDGF)-B (39), and connective tissue growth factor (CTGF) (45). These abnormalities may be interconnected; and TGF-␤ may be a proximal trigger.…”

mentioning

confidence: 99%

PTEN loss defines a TGF-β-induced tubule phenotype of failed differentiation and JNK signaling during renal fibrosis

Lan

Geng

Polichnowski

et al. 2012

American Journal of Physiology-Renal Physiology

102

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We investigated the signaling basis for tubule pathology during fibrosis after renal injury. Numerous signaling pathways are activated physiologically to direct tubule regeneration after acute kidney injury (AKI) but several persist pathologically after repair. Among these, transforming growth factor (TGF)-β is particularly important because it controls epithelial differentiation and profibrotic cytokine production. We found that increased TGF-β signaling after AKI is accompanied by PTEN loss from proximal tubules (PT). With time, subpopulations of regenerating PT with persistent loss of PTEN (phosphate and tension homolog) failed to differentiate, became growth arrested, expressed vimentin, displayed profibrotic JNK activation, and produced PDGF-B. These tubules were surrounded by fibrosis. In contrast, PTEN recovery was associated with epithelial differentiation, normal tubule repair, and less fibrosis. This beneficial outcome was promoted by TGF-β antagonism. Tubule-specific induction of TGF-β led to PTEN loss, JNK activation, and fibrosis even without prior AKI. In PT culture, high TGF-β depleted PTEN, inhibited differentiation, and activated JNK. Conversely, TGF-β antagonism increased PTEN, promoted differentiation, and decreased JNK activity. Cre-Lox PTEN deletion suppressed differentiation, induced growth arrest, and activated JNK. The low-PTEN state with JNK signaling and fibrosis was ameliorated by contralateral nephrectomy done 2 wk after unilateral ischemia, suggesting reversibility of the low-PTEN dysfunctional tubule phenotype. Vimentin-expressing tubules with low-PTEN and JNK activation were associated with fibrosis also after tubule-selective AKI, and with human chronic kidney diseases of diverse etiology. By preventing tubule differentiation, the low-PTEN state may provide a platform for signals initiated physiologically to persist pathologically and cause fibrosis after injury.

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Role of Atrophic Tubules in Development of Interstitial Fibrosis in Microembolism-Induced Renal Failure in Rat

Cited by 51 publications

References 39 publications

Autophagy Regulates TGF-β Expression and Suppresses Kidney Fibrosis Induced by Unilateral Ureteral Obstruction

Autophagy Regulates TGF-β Expression and Suppresses Kidney Fibrosis Induced by Unilateral Ureteral Obstruction

Severe Renal Mass Reduction Impairs Recovery and Promotes Fibrosis after AKI

PTEN loss defines a TGF-β-induced tubule phenotype of failed differentiation and JNK signaling during renal fibrosis

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