Overexpression of Toll-like receptor 8 correlates with the progression of podocyte injury in murine autoimmune glomerulonephritis

Kimura, Junko; Ichii, Osamu; Miyazono, Kosuke; Nakamura, Teppei; Horino, Taro; Otsuka-Kanazawa, Saori; Kon, Yasuhiro

doi:10.1038/srep07290

Cited by 28 publications

(24 citation statements)

References 38 publications

(68 reference statements)

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“…Paraffin-embedded kidney sections were stained with periodic acid Schiff (PAS) or Masson’s trichrome for histopathological analysis, and the area of renal pelvis (RP) was measured using ImageJ (NIH) or BZ-H3M (Keyence; Osaka, Japan). Sections were analyzed by immunohistochemistry or immunofluorescence using primary antibodies listed in Table S3 in Supplementary Material as described previously ( 9 , 16 ) and evaluated for the number of B220 + cells, Gr1 + cells, Iba1 + cells, single strand DNA (ssDNA) + cells, Caspase 3 + cells, and IL-36α + tubules. The signals detected in areas positive for CD3, BrdU, alpha-smooth muscle actin (αSMA), and IL-36α were measured by using ImageJ (NIH) or BZ-H3M (Keyence).…”

Section: Methodsmentioning

confidence: 99%

IL-36α Regulates Tubulointerstitial Inflammation in the Mouse Kidney

et al. 2017

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IL-36α, a member of the IL-1 family, is a crucial mediator of inflammatory responses. We previously found that IL-36α was overexpressed in injured distal tubules (DTs); however, its pathological function remains unclear. Herein, unilateral ureter obstruction (UUO) or folic acid (FA) injection was performed in mouse kidneys to assess the role of IL-36α in kidney injury. IL-36α mRNA and protein expression significantly increased in the kidneys within 24 h after UUO. IL-36α localized to dilated DTs. IL-36α expression significantly correlated with the progression of tubulointerstitial cell infiltration and tubular epithelium cell death in UUO kidneys and with renal dysfunction in FA-induced acute kidney injury mice. At 24 h after UUO, IL-36α+ DT epithelial cells showed loose intercellular digitations. IL-1RL2, an IL-36α receptor protein, localized to podocytes, proximal tubules, and DTs in the healthy kidney. IL-1RL2 was expressed in interstitial cells and platelets or extended primary cilia of DT epithelial cells in UUO kidneys. IL-36α stimulation promoted the production of IL-6 and Prss35, an inflammatory cytokine and collagen remodeling-associated enzyme, respectively, in cultured NIH3T3 fibroblasts. UUO-treated IL-36α-knockout (KO) mice showed milder kidney injury features than wild-type (WT) mice did. In UUO kidneys from IL-36α-KO mice, the expression of genes associated with inflammatory response and sensory perception was significantly different from that in WT mice. Altogether, our data indicate an association between intrarenal IL-36α overexpression and the progression of tubulointerstitial inflammations and morpho-functional alterations of DT epithelial cells. IL-36α may be a novel kidney injury marker useful for evaluating DT damages.

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Section: Methodsmentioning

confidence: 99%

IL-36α Regulates Tubulointerstitial Inflammation in the Mouse Kidney

et al. 2017

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“…Estrogen treatment has been found to increases the expression level of TLR8 [ 100 ]. Notably, overexpression of TLR8 is correlated with local injury in glomerulonephritis [ 101 ].…”

Section: B Cell-intrinsic Tlr Signals In Lupusmentioning

confidence: 99%

Roles of B Cell-Intrinsic TLR Signals in Systemic Lupus Erythematosus

Fang

et al. 2015

IJMS

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Toll-like receptors (TLRs) are a large family of pattern recognition receptors. TLR signals are involved in the pathogenesis of systemic lupus erythematosus. Mouse and human B cells constitutively express most TLRs. Many B cell subpopulations are highly responsive to certain TLR ligation, including B-1 B cells, transitional B cells, marginal zone B cells, germinal center B cell and memory B cells. The B cell-intrinsic TLR signals play critical roles during lupus process. In this review, roles of B cell-intrinsic TLR2, 4, 7, 8 and 9 signals are discussed during lupus pathogenesis in both mouse model and patients. Moreover, mechanisms underlying TLR ligation-triggered B cell activation and signaling pathways are highlighted.

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“…Mice of this strain develop systemic autoimmune disease characterised by increased serum autoantibody titres, autoreactive B cells, vasculitis, and podocyte injury 4 with MPGN. Yaa carries a genetic mutation on the Y chromosome called “Y-linked autoimmune acceleration” ( Yaa) , and male mice develop more severe MPGN than female mice due to the Yaa mutation 16 – 19 . The present study clearly revealed pathological correlations between the glomerular endothelial and podocyte injury in MPGN pathogenesis through a unique ultrastructural analysis and molecular quantitative analysis.…”

Section: Introductionmentioning

confidence: 99%

Modified scanning electron microscopy reveals pathological crosstalk between endothelial cells and podocytes in a murine model of membranoproliferative glomerulonephritis

Masum

Ichii

Elewa

et al. 2018

Sci Rep

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This study evaluated endothelial cells and podocytes, both being primary components of the glomerular filtration barrier, in the progression of membranoproliferative glomerulonephritis (MPGN) using modified scanning electron microscopy (mSEM) analysis. BXSB/MpJ-Yaa model mice exhibited autoimmune-mediated MPGN characterised by elevated serum autoantibody levels, albuminuria, renal dysfunctional parameters, and decreased glomerular endothelial fenestrations (EF) and podocyte foot process (PFP) effacement with immune cell infiltration. Similar to transmission electron microscopy, mSEM revealed a series of pathological changes in basement membrane and densities of EF and PFP in BXSB/MpJ-Yaa compared with control BXSB/MpJ at different stages. Further, immunopositive area of endothelial marker (CD34), podocyte functional molecules (Nephrin, Podocin, Synaptopodin, and Wilms’ tumour 1 (WT1)), and vascular endothelial growth factor A (VEGF A) significantly decreased in the glomerulus of BXSB/MpJ-Yaa compared with BXSB at final stage. The indices of glomerular endothelial injuries (EF density and immunopositive area of CD34 and VEGF A) and podocyte injuries (PEP density and immunopositive area of podocyte functional molecules) were also significantly correlated with each other and with indices of autoimmune disease and renal dysfunction. Thus, our results elucidated the pathological crosstalk between endothelial cells and podocytes in MPGN progression and the usefulness of mSEM for glomerular pathological analysis.

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Overexpression of Toll-like receptor 8 correlates with the progression of podocyte injury in murine autoimmune glomerulonephritis

Cited by 28 publications

References 38 publications

IL-36α Regulates Tubulointerstitial Inflammation in the Mouse Kidney

IL-36α Regulates Tubulointerstitial Inflammation in the Mouse Kidney

Roles of B Cell-Intrinsic TLR Signals in Systemic Lupus Erythematosus

Modified scanning electron microscopy reveals pathological crosstalk between endothelial cells and podocytes in a murine model of membranoproliferative glomerulonephritis

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