Heme oxygenase-1 induction contributes to renoprotection by G-CSF during rhabdomyolysis-associated acute kidney injury

Wei, Qingqing; Hill, William; Su, Yunchao; Huang, Shuang; Dong, Zheng

doi:10.1152/ajprenal.00438.2010

Cited by 50 publications

(47 citation statements)

References 42 publications

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“…Glycerol induces damage by oxidative stress, apoptosis, and inflammation is key mediator of renal dysfunction [40][41][42][43][44][45]. The association between oxidative stress and nephrotoxicity has been well established in many experimental animal models.…”

Section: Discussionmentioning

confidence: 99%

Antioxidant and Nephroprotective Activities of Aconitum heterophyllum Root in Glycerol Induced Acute Renal Failure in Rats

Konda

Eerike

Raghuraman

et al. 2016

JCDR

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Section: Discussionmentioning

confidence: 99%

Antioxidant and Nephroprotective Activities of Aconitum heterophyllum Root in Glycerol Induced Acute Renal Failure in Rats

Konda

Eerike

Raghuraman

et al. 2016

JCDR

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“…Recent studies indicate that blood-borne infiltrating cells play an important role in kidney protection. 55,56 In rhabdomyolysis, the cell-protective enzyme Hmox-1 is upregulated in renal proximal tubules 16,57 in the absence of HIF. 16 In conclusion, a genome-wide search for potentially renalprotective genes in early stages after the onset of AKI provides strong evidence for a metabolic shift toward anaerobic energy metabolism in tubules at risk as the main mechanism of renal protection through VHL knockout.…”

Section: Discussionmentioning

confidence: 99%

Tubular von Hippel-Lindau Knockout Protects against Rhabdomyolysis-Induced AKI

Fähling¹,

Mathia

Paliege

et al. 2013

Journal of the American Society of Nephrology

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Renal hypoxia occurs in AKI of various etiologies, but adaptation to hypoxia, mediated by hypoxiainducible factor (HIF), is incomplete in these conditions. Preconditional HIF activation protects against renal ischemia-reperfusion injury, yet the mechanisms involved are largely unknown, and HIF-mediated renoprotection has not been examined in other causes of AKI. Here, we show that selective activation of HIF in renal tubules, through Pax8-rtTA-based inducible knockout of von Hippel-Lindau protein (VHL-KO), protects from rhabdomyolysis-induced AKI. In this model, HIF activation correlated inversely with tubular injury. Specifically, VHL deletion attenuated the increased levels of serum creatinine/urea, caspase-3 protein, and tubular necrosis induced by rhabdomyolysis in wild-type mice. Moreover, HIF activation in nephron segments at risk for injury occurred only in VHL-KO animals. At day 1 after rhabdomyolysis, when tubular injury may be reversible, the HIF-mediated renoprotection in VHL-KO mice was associated with activated glycolysis, cellular glucose uptake and utilization, autophagy, vasodilation, and proton removal, as demonstrated by quantitative PCR, pathway enrichment analysis, and immunohistochemistry. In conclusion, a HIF-mediated shift toward improved energy supply may protect against acute tubular injury in various forms of AKI. 24: 180624: -181924: , 201324: . doi: 10.1681 No specific therapy is currently available for human AKI, a clinical entity of increasing incidence and high morbidity and mortality. 1-4 Rhabdomyolysis, one of the leading causes of AKI, develops after trauma, drug toxicity, infections, burns, and physical exertion. [5][6][7][8] The animal model using an intramuscular glycerol injection with consequent myoglobinuria is closely related to the human syndrome of rhabdomyolysis. 9 Experimental data demonstrate renal vasoconstriction, 9-15 tubular hypoxia, 15,16 normal or even reduced intratubular pressure, 9-11 as well as large variation in single nephron GFR. 10,11 Intratubular myoglobin casts, a histologic hallmark, seem not to cause tubular obstruction, 9-11 but rather scavenge nitric oxide 17,18 and generate reactive oxygen species 19 followed by vasoconstriction. J Am Soc NephrolThe traditional discrimination between ischemic and toxic forms of AKI has been challenged because an increasing amount of evidence suggests that renal hypoxia is a common denominator in AKI of different etiologies. 20 Pimonidazole adducts, which accumulate in tissues at oxygen tensions ,10 mmHg, 21 have been demonstrated in various AKI forms. 16,[22][23][24] During AKI, hypoxia-inducible factors (HIFs), which are mainly regulated by oxygen-dependent proteolysis, were found to be upregulated in different renal tubular segments. 16,20,22,24,25 HIFs are heterodimers of a constitutive b subunit, HIF-b (ARNT), and one of three oxygen-dependent a-subunits, HIF-1a, HIF-2a, and HIF-3a. The a-b dimers bind to hypoxia-response elements (HREs) in the promoter-enhancer region of HIF target genes. [26][27]...

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“…To induce rhabdomyolysis, the animals were intramuscularly injected in each thigh caudal muscle with 7.5 ml/kg 50% glycerol (99.5% m/v AnalaR Normapur; VWR International S.A.S., Fontenay sous Bois, France) or saline as a control. 42 To study the effect of clodronate, a macrophage-depleting drug, liposomal clodronate (Clodrosome) or the same volume of control liposome suspension (Encapsome; Encapsula Nanosciences LLC, Nashville, TN), was administered intraperitoneally to the animals as a full dose (40 mg/kg) the day before the glycerol injection or a half-dose (20 mg/kg) the day after the glycerol injection, according to previously published protocols. 43 …”

Section: Animal Modelmentioning

confidence: 99%

Specific Macrophage Subtypes Influence the Progression of Rhabdomyolysis-Induced Kidney Injury

Béllière¹,

Casemayou²,

Ducassé³

et al. 2015

Journal of the American Society of Nephrology

130

123

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Rhabdomyolysis can be life threatening if complicated by AKI. Macrophage infiltration has been observed in rat kidneys after glycerol-induced rhabdomyolysis, but the role of macrophages in rhabdomyolysisinduced AKI remains unknown. Here, in a patient diagnosed with rhabdomyolysis, we detected substantial macrophage infiltration in the kidney. In a mouse model of rhabdomyolysis-induced AKI, diverse renal macrophage phenotypes were observed depending on the stage of the disease. rophages. Furthermore, transcriptionally regulated targets potentially involved in disease progression, including fibronectin, collagen III, and chemoattractants that were identified via single-cell analysis, were verified as macrophage-dependent in situ. In vitro, myoglobin treatment induced proximal tubular cells to secrete chemoattractants and macrophages to express proinflammatory markers. At day 30, liposomal clodronate-mediated macrophage depletion reduced fibrosis and improved both kidney repair and mouse survival. Seven months after rhabdomyolysis, histologic lesions were still present but were substantially reduced with prior depletion of macrophages. These results suggest an important role for macrophages in rhabdomyolysisinduced AKI progression and advocate the utility of long-term follow-up for patients with this disease.

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Heme oxygenase-1 induction contributes to renoprotection by G-CSF during rhabdomyolysis-associated acute kidney injury

Cited by 50 publications

References 42 publications

Antioxidant and Nephroprotective Activities of Aconitum heterophyllum Root in Glycerol Induced Acute Renal Failure in Rats

Antioxidant and Nephroprotective Activities of Aconitum heterophyllum Root in Glycerol Induced Acute Renal Failure in Rats

Tubular von Hippel-Lindau Knockout Protects against Rhabdomyolysis-Induced AKI

Specific Macrophage Subtypes Influence the Progression of Rhabdomyolysis-Induced Kidney Injury

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