Depletion of Macrophages and Dendritic Cells in Ischemic Acute Kidney Injury

Lu, Lawrence; Faubel, Sarah; He, Zhibin; Andrés-Hernando, Ana; Jani, Alkesh; Kedl, Ross M.; Edelstein, Charles L.

doi:10.1159/000335582

Cited by 53 publications

(52 citation statements)

References 49 publications

(27 reference statements)

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“…CXCL1 exhibits neutrophil chemoattractant activity (27,32), eliciting its effects through the chemokine receptor CXCR2 (39) in angiogenesis and in inflammation (50). It had a significant influence on the inflammatory responses in models of acute renal failure (26), as well as in a nephrotoxic nephritis model in rats (49). It is also likely to be important in renal inflammation because of other disease processes, such as malignant hypertension (18).…”

Section: Discussionmentioning

confidence: 99%

Impaired excitability of renal afferent innervation after exposure to the inflammatory chemokine CXCL1

Ditting

Freisinger

Rodionova

et al. 2016

American Journal of Physiology-Renal Physiology

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Recently, we showed that renal afferent neurons exhibit a unique firing pattern, i.e., predominantly sustained firing, upon stimulation. Pathological conditions such as renal inflammation likely alter excitability of renal afferent neurons. Here, we tested whether the proinflammatory chemokine CXCL1 alters the firing pattern of renal afferent neurons. Rat dorsal root ganglion neurons (Th11-L2), retrogradely labeled with dicarbocyanine dye, were incubated with CXCL1 (20 h) or vehicle before patchclamp recording. The firing pattern of neurons was characterized as tonic, i.e., sustained action potential (AP) firing, or phasic, i.e., Ͻ5 APs following current injection. Of the labeled renal afferents treated with vehicle, 58.9% exhibited a tonic firing pattern vs. 7.8%, in unlabeled, nonrenal neurons (P Ͻ 0.05). However, after exposure to CXCL1, significantly more phasic neurons were found among labeled renal neurons; hence the occurrence of tonic neurons with sustained firing upon electrical stimulation decreased (35.6 vs. 58.9%, P Ͻ 0.05). The firing frequency among tonic neurons was not statistically different between control and CXCL1-treated neurons. However, the lower firing frequency of phasic neurons was even further decreased with CXCL1 exposure [control: 1 AP/600 ms (1-2) vs. CXCL1: 1 AP/600 ms (1-1); P Ͻ 0.05; median (25th-75th percentile)]. Hence, CXCL1 shifted the firing pattern of renal afferents from a predominantly tonic to a more phasic firing pattern, suggesting that CXCL1 reduced the sensitivity of renal afferent units upon stimulation. chemokine; CXCL1; renal afferent nerve; voltage-gated sodium channel; tonic; phasic; firing pattern OBSERVATIONS IN PATIENTS with renal failure and/or hypertension who were nephrectomized (7, 17) strongly suggest that renal sensory afferent innervation increases sympathetic-mediated vasoconstriction. Moreover, sympathetic nerve activity in patients after renal transplantation was only normalized with concomitant bilateral nephrectomy (17). Additional work in experimental models indicated (21, 23) that efferent neurogenic influences on cardiac pathology in renal insufficiency are mediated by renal afferent nerve activity (1).In experimental animals, afferent innervation of the kidney was reported to contribute to the sustained blood pressure increases when renal structural damage was present (3, 46). In contrast, renal afferent nerves were described to act protectively against salt-sensitive hypertension and the structural renal damage of high blood pressure (24,44). A more recent study using a more selective method of renal afferent denervation suggests that this might not be the case, but it could be shown that selective renal afferent denervation was able to blunt the development of deoxycorticosterone acetate-salt hypertension (12).Therefore, the benefit of afferent renal nerve ablation for the treatment of refractory hypertension remains controversial (31). In any case, the modulatory influence of afferent renal nerves on sympathetic tone is not well understood....

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Section: Discussionmentioning

confidence: 99%

Impaired excitability of renal afferent innervation after exposure to the inflammatory chemokine CXCL1

Ditting

Freisinger

Rodionova

et al. 2016

American Journal of Physiology-Renal Physiology

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“…For example, one study revealed that suppression of macrophage recruitment in osteopontin-knockout mice reduces tubulointerstitial fibrosis during the recovery process of IRI (100). Several other studies confirmed that macrophages are involved in the kidney repair after IRI in that macrophage ablation by either LC or diphtheria toxin 48 -72 h after IRI resulted in persistent kidney injury (67,83,127). Lee found that depletion of macrophages at the time of IRI (when M1 macrophages are predominant) attenuated kidney injury, whereas depletion during the repair phase (when M2 macrophages are predominant) delayed kidney repair (75).…”

Section: Anti-inflammatory Macrophages Mediate Kidney Repair and Regementioning

confidence: 99%

Macrophages in Kidney Injury, Inflammation, and Fibrosis

2015

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Macrophages are found in normal kidney and in increased numbers in diseased kidney, where they act as key players in renal injury, inflammation, and fibrosis. Macrophages are highly heterogeneous cells and exhibit distinct phenotypic and functional characteristics in response to various stimuli in the local microenvironment in different types of kidney disease. In kidney tissue necrosis and/or infection, damage- and/or pathogen-associated molecular patterns induce pro-inflammatory macrophages, which contribute to further tissue injury, inflammation, and subsequent fibrosis. Apoptotic cells and anti-inflammatory factors in post-inflammatory tissues induced anti-inflammatory macrophages, which can mediate kidney repair and regeneration. This review summarizes the role of macrophages with different phenotypes in kidney injury, inflammation, and fibrosis in various acute and chronic kidney diseases. Understanding alterations of kidney microenvironment and the factors that control the phenotype and functions of macrophages may offer an avenue for the development of new cellular and cytokine/growth factor-based therapies as alternative treatment options for patients with kidney disease.

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“…9,10 Mononuclear cell depletion was associated with the exacerbation of kidney lesions induced by cisplatin or acute GN, suggesting a protective role for these cells. 11,12 Conversely, macrophage depletion was associated with the reduction of lesions in obstructive nephropathy 13 and ischemic AKI, 14 suggesting that macrophages exacerbate AKI. Taken together, depletion experiments in AKI have led to conflicting data and demonstrate the need of additional studies to define macrophage subtypes.…”

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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

126

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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Depletion of Macrophages and Dendritic Cells in Ischemic Acute Kidney Injury

Cited by 53 publications

References 49 publications

Impaired excitability of renal afferent innervation after exposure to the inflammatory chemokine CXCL1

Impaired excitability of renal afferent innervation after exposure to the inflammatory chemokine CXCL1

Macrophages in Kidney Injury, Inflammation, and Fibrosis

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

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