Crystal-induced inflammation of the kidneys: results from human studies, animal models, and tissue-culture studies

Abstract

Calcium oxalate (CaOx), calcium phosphate (CaP), and uric acid or urate are the most common crystals seen in the kidneys. Most of the crystals evoke an inflammatory response leading to fibrosis, loss of nephrons, and eventually to chronic renal failure. Of the three, CaOx monohydrate is the most reactive, whereas some forms of CaP do not evoke any discernible response. Reactive oxygen species are produced during the interactions between the crystals and renal cells and are responsible for the various cellular responses. CaOx crystals generally form in the renal tubules. Exposure of renal epithelial cells to CaOx crystals results in the increased synthesis of osteopontin, bikunin, heparan sulfate, monocyte chemoattractant protein 1 (MCP-1), and prostaglandin (PG) E2, which are known to participate in inflammatory processes and in extracellular matrix production. CaOx crystal deposition in rat kidneys also activates the renin-angiotensin system. Both Ox and CaOx crystals selectively activate p38 mitogen-activated protein kinase (MAPK) in exposed tubular cells. CaP crystals can form in the tubular lumen, tubular cells, or tubular basement membrane. Renal epithelial cells exposed to brushite crystals produce MCP-1. Basic CaP and calcium pyrophosphate dihydrate induce mitogenesis in fibroblasts, stimulate production of PGE2, and up-regulate the synthesis of metalloproteinases (MMP) while down-regulating the production of inhibitors of MMPs through activation of p42/44 MAPK. Deposition of urate crystals in the kidneys becomes associated with renal tubular atrophy, interstitial fibrosis, and development of inflammatory infiltrate. Renal epithelial cells exposed to uric acid crystals synthesize MCP-1 as well as PGE2. Monocytes or neutrophils exposed to urate crystals produce tumor necrosis factor alpha, interleukin-1 (IL-1), IL-6, and IL-8. Expression of IL-8 is mediated through extracellular signal-regulated kinase 1 (ERK-1)/ERK-2 and nuclear transcription factors activated protein 1 and nuclear factor kappabeta. Urate crystals also stimulate the macrophages to produce MMPs.

Role of extracellular membrane vesicles in the pathogenesis of various diseases, including cancer, renal diseases, atherosclerosis, and arthritis

“…83 Crystal deposition in the kidneys can induce tubulointerstitial damage and inflammation, leading to fibrosis, loss of nephrons, and chronic renal failure. 84 In vitro studies have demonstrated that renal brush border MVs B100 nm in diameter, 85 can induce and promote CaOx crystallization. 86 It is not known whether such MVs also initiate CaP or urate crystal stones.…”

Mouse interleukin-20 receptor 1a targets renal epithelial cells and is associated with renal calcium deposition

“…28. Transgenic mice showed that the overexpression of mIL-20R1a facilitated the accumulation of calcium in renal tubules.…”

“…28 In response to CaOx exposure, renal epithelial cells produce a variety of cytokines and chemoattractants to recruit immune (Figures 7a and b), whereas IL-6 transcripts were increased only in mIL-20R1a-treated TKPTS cells (Po0.05) ( Figure 7B). The expression of TNF-a, MCP-1 and RANTES in CaOx-exposed M-1 cells and that of IL-6, TNF-a, MCP-1 and RANTES in CaOx-exposed TKPTS cells further increased after 4 h of mIL-20R1a treatment (Po0.05) (Figure 7a and b).…”

“…27 Furthermore, crystal deposition is often associated with inflammation. 28 Diverse inflammatory cells migrating to the adjacent interstitium are important in renal tissue damage. 28 CaOx-induced peroxidative injury because of ROS production is one major mechanism that promotes crystal attachment to renal epithelial cells.…”

“…28 Diverse inflammatory cells migrating to the adjacent interstitium are important in renal tissue damage. 28 CaOx-induced peroxidative injury because of ROS production is one major mechanism that promotes crystal attachment to renal epithelial cells. 29 Calcium-induced injury exposes the basolateral membrane, which often becomes the site of an anchored aggregation of crystals.…”