Immunoglobulin light chains generate proinflammatory and profibrotic kidney injury
Wei-Zhong Ying, … , Lisa M. Curtis, Paul W. Sanders
Wei-Zhong Ying, … , Lisa M. Curtis, Paul W. Sanders
Published April 16, 2019
Citation Information: J Clin Invest. 2019;129(7):2792-2806. https://doi.org/10.1172/JCI125517.
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Research Article Hematology Nephrology

Immunoglobulin light chains generate proinflammatory and profibrotic kidney injury

Abstract

Because of the less-than-robust response to therapy and impact on choice of optimal chemotherapy and prognosis, chronic kidney disease has drawn attention in the treatment of multiple myeloma, a malignant hematologic disorder that can produce significant amounts of monoclonal immunoglobulin free light chains (FLCs). These low-molecular-weight proteins are relatively freely filtered through the glomerulus and are reabsorbed by the proximal tubule. The present study demonstrated that during the process of metabolism of immunoglobulin FLCs, ROS activated the STAT1 pathway in proximal tubule epithelium. STAT1 activation served as the seminal signaling molecule that produced the proinflammatory molecule IL-1β, as well as the profibrotic agent TGF-β by this portion of the nephron. These effects occurred in vivo and were produced specifically by the generation of hydrogen peroxide by the VL domain of the light chain. To the extent that the experiments reflect the human condition, these studies offer insights into the pathogenesis of progressive kidney failure in the setting of lymphoproliferative disorders, such as multiple myeloma, that feature increased circulating levels of monoclonal immunoglobulin fragments that require metabolism by the kidney.

Authors

Wei-Zhong Ying, Xingsheng Li, Sunil Rangarajan, Wenguang Feng, Lisa M. Curtis, Paul W. Sanders

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Figure 3

Knockdown of STAT1 inhibits FLC-mediated increases in TGF-β in medium and p-STAT1 and p-SMAD2 levels in HK-2 cells.

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Knockdown of STAT1 inhibits FLC-mediated increases in TGF-β in medium an...
(A) All tested FLCs increased active TGF-β by HK-2 cells treated with a nontargeting siRNA, but not by HK-2 cells pretreated with an siRNA that targeted STAT1 (n = 5–6 in each group). Data are expressed as the mean ± SEM. Factorial ANOVA comparing the main effects of the FLC and the interaction effect between the FLC and siRNA on TGF-β showed that all effects were significant at a P value of less than 0.0001. The main effect for the siRNA yielded an F ratio of F(1, 66) = 6203, P < 0.0001. The interaction effect was significant: F(6, 66) = 185.8, P < 0.001. *P < 0.0001 compared with the corresponding group. (B) Western blot and (C) densitometric analyses showed the effect of siRNA treatment on p-STAT1 and p-SMAD2 (n = 4 in each group). Data are expressed as the mean ± SEM. Factorial ANOVA comparing the main effects of the FLC and the interaction effect between the FLC and siRNA on p-STAT1 showed that the main effect for the FLC yielded an F ratio of F(2, 18) = 3.724, P = 0.044, and that the effect of the siRNA yielded an F ratio of F(1, 18) = 0.0001. The interaction effect was not significant. *P = 0.014 compared with the corresponding group. For p-SMAD2, factorial ANOVA comparing the main effects of the FLC and the interaction effect between the FLC and the siRNA showed that all effects were significant at a P value of less than 0.0001. The main effect for the siRNA yielded an F ratio of F(1, 18) = 194.3, P < 0.0001. The interaction effect was significant at F(2, 18) = 32.19, P < 0.0001. *P < 0.0001 compared with the corresponding group.