Cisplatin-induced nephrotoxicity is mediated by tumor necrosis factor-α produced by renal parenchymal cells

Abstract

Cisplatin is a chemotherapeutic agent that induces tumor necrosis factor-alpha (TNF-alpha) production in many cell types with unfortunate renal toxicity. We sought to determine the contributions of renal parenchymal cells and bone marrow-derived immune cells to the pathogenesis of cisplatin-induced renal injury in vivo. To do this we created chimeric mice in which the bone marrow was ablated and replaced with donor bone marrow cells from wild-type or from TNF-alpha knockout mice. Six weeks after reconstitution, the chimeric mice were treated with cisplatin and renal structural and functional parameters were measured. Chimeras with kidneys of wild-type animals all developed significant renal failure after 72 h of cisplatin treatment regardless of the immune cell source. Chimeras with kidneys of TNF-alpha knockout mice showed significantly less renal dysfunction (blood urea nitrogen, serum creatinine, and glomerular filtration rate), renal histologic injury, and serum TNF-alpha levels; again regardless of the immune cell source. Urinary excretion of several proinflammatory cytokines was lower in the wild-type bone marrow-knockout kidney chimera mouse than in wild-type background mice. Our results indicate that a substantial portion of circulating and urinary TNF-alpha is derived from nonimmune cells after cisplatin administration. We conclude that the production of TNF-alpha by renal parenchymal cells, rather than by bone marrow-derived infiltrating immune cells, is responsible for cisplatin-induced nephrotoxicity.

Competing Actions of Type 1 Angiotensin II Receptors Expressed on T Lymphocytes and Kidney Epithelium during Cisplatin-Induced AKI

“…Although the alterations in systemic TNF levels could accrue directly from enhanced generation in the distal nephron, the dramatic effects of TNF deletion in the nephron on systemic TNF levels would suggest additional secondary effects related to either downstream immune activation or reduced TNF clearance with worsening renal parenchymal injury. Our findings corroborate the elegant murine chimera study from Zhang et al 6 showing that TNF produced by nonhematopoietic cells is responsible for cisplatin nephrotoxicity. To our knowledge, however, these experiments provide the first direct evidence that the renal tubular epithelium triggers its own demise during cisplatin therapy via the local generation of TNF.…”

“…3,4 In this regard, TNF-a plays a central role in mediating cisplatininduced renal damage. 5,6 Our recent experiments have suggested that actions of the renin-angiotensin system (RAS) are tissue dependent in the setting of various CKDs. [7][8][9] Despite the wide use of RAS inhibitors, including type 1 angiotensin receptor blockers (ARBs), little evidence is available to direct the use of these medicines when a patient is at risk of developing AKI.…”

Renal Dendritic Cells Ameliorate Nephrotoxic Acute Kidney Injury

“…This finding has important implications for the design and interpretation of bone marrow chimera studies, which are being increasingly applied to the study of kidney disease. 4,34,59 During tissue injury, inflammatory DCs may be recruited to the sites of inflammation. 12,27,28 In addition, danger signals released from dying cells may stimulate DCs 37,60,61 ; however, we found that depletion of DCs 24 h after cisplatin treatment did not ameliorate cisplatin toxicity and that few inflammatory DCs could be identified.…”

“…In response to renal injury, inflammatory chemokines and cytokines are produced both by renal parenchymal cells, such as proximal tubule epithelial cells, and resident or infiltrating leukocytes. [1][2][3][4] The elaborated chemokines and cytokines, including TNF-␣, IL-18, keratinocyte-derived chemokine, and monocyte chemoattractant protein 1, subsequently recruit additional immune cells to the kidney, such as neutrophils, T cells, monocytes, and inflammatory dendritic cells (DCs), which may cause further injury through pathways that are not fully defined. 2,[5][6][7][8][9][10][11][12] DCs are sentinels of the immune system and under steady-state conditions induce tolerance by various mechanisms, including production of TGF-␤, IL-10, or indoleamine 2,3-dioxygenase [13][14][15][16] ; expression of PDL-1, PDL-2, or Fc␥R2B 17,18 ; clonal deletion of autoreactive T cells 19 ; and induction of T regulatory cells via the inducible co-stimulator (ICOS) pathway.…”

“…12, 23 We have reported that inflammation plays an important role in the pathogenesis of cisplatin-induced acute kidney injury (AKI). 1,4,5,34 Given the dearth of information regarding the role of renal DCs in AKI, this study examined the renal DC population and the impact of its depletion on cisplatin nephrotoxicity. We show that DCs are the most abundant population of renal resident leukocytes and form a dense network throughout the tubulointerstitium.…”