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Simple Summary: Paraneoplastic nephrotic syndrome is a complication arising in lung cancer patients. In the present study, we established an LLC1 cell orthotopic xenograft C57BL/6 mice model to translation paraneoplastic nephrotic syndrome (PNS). The pathological aspects of PNS were characterized in TGF-β signaling-engaged renal fibrosis, and renal inflammation with IL-6 expression in kidney. To reveal how the lung cancer cells remotely drive pathogenic progression, secretome derived from LLC1 cells and A549 cells were proteomically profiled. Additionally, the secretome profiling was subjected to diseases and biofunctions assessment by Ingenuity Pathway analysis (IPA). As matter of secretome profiling and IPA prediction, the Fibronectin, C1r, and C1s are potential of nephrotoxicity linked to paraneoplastic effects on glomerular pathogenesis in these lung cancer mice. Kidney failure is a possible but rare complication in lung cancer patients that may be caused by massive tumor lysis or a paraneoplastic effect. Clinical case reports have documented pathological characteristics of paraneoplastic syndrome in glomeruli, but are short of molecular details. When Lewis lung carcinoma 1 (LLC1) cells were implanted in mice lungs to establish lung cancer, renal failure was frequently observed two weeks post orthotopic xenograft. The high urinary albumin-to-creatinine ratio (ACR) was diagnosed as paraneoplastic nephrotic syndrome in those lung cancer mice. Profiling the secretome of the lung cancer cells revealed that the secretory proteins were potentially nephrotoxic. The nephrotoxicity of lung cancer-derived secretory proteins was tested by examining the pathogenic effects of 1 × 106, 2 × 106, and 5 × 106 LLC1 cell xenografts on the pathogenic progression in kidneys. Severe albuminuria was present in the mice that received 5 × 106 LLC1 cells implantation, whereas 106 cell and 2 × 106 cell-implanted mice have slightly increased albuminuria. Pathological examinations revealed that the glomeruli had capillary loop collapse, tumor antigen deposition in glomeruli, and renal intratubular casts. Since IL-6 and MCP-1 are pathologic markers of glomerulopathy, their distributions were examined in the kidneys of the lung cancer mice. Moderate to severe inflammation in the kidneys was correlated with increases in the number of cells implanted in the mice, which was reflected by renal IL-6 and MCP-1 levels, and urine ACR. TGF-β signaling-engaged renal fibrosis was validated in the lung cancer mice. These results indicated that lung cancer cells could provoke inflammation and activate renal fibrosis. [ABSTRACT FROM AUTHOR]