發炎反應加劇高鈣誘導的腎臟成骨化參與磷酸鈣結石形成

曾一修^1,2,3、曾馨儀^1,4、陳吟佩^1,4、盧艷金^1,4

亞東紀念醫院外科部創傷科¹與泌尿科²; 元智大學醫學研究所³; 亞東紀念醫院醫學研究部⁴

Inflammation Accelerated Renal Osteogenesis Induced by Calcium via MAPK Pathway in the Development of Calcium Phosphate Stones

Yi-Shiou Tseng^1,2,3, Hsing-I Tseng^1,4, Yin-Pei Chen^1,4, Yen-Chin Lu^1,4

Divisions of Traumatology¹ and Urology², Far Eastern Memorial Hospital; Graduate Institute of Medicine, Yuan Ze University³; Department of Medical Research⁴, Far Eastern Memorial Hospital

Purpose: 57% to 74% of kidney stones initiate and form on Randall's plaques, which are calcium phosphate (CaP) structures deposited in the renal interstitium and extending to the renal papillary surface. While inflammation and osteogenesis have been proposed as participants in Randall's plaque formation, their interrelationship remained unclear. In vascular calcification, sharing similar pathological mechanisms with Randall's plaque, studies have shown that pro-inflammatory cytokines upregulated the expression of osteogenesis-related protein during cell calcification. However, the same mechanisms have not yet been explored in Randall's plaque. In this research, we explored the mechanism underlying CaP stone formation.

Materials and Methods: To investigate whether inflammation promotes renal CaP deposition, we induced renal inflammation by unilateral ureteral obstruction (UUO) surgery on the first day and fed rats a high-calcium diet for 4 weeks. Renal calcium deposition was examined by Von Kossa staining and micro-FTIR. Immunohistochemistry staining and Western blot analysis were performed to assess the levels of osteogenesis and inflammation markers in the kidneys. Additionally, we stimulated HK-2 renal tubular epithelial cells with pro-inflammatory cytokines to explore the signaling pathways involved in the osteogenesis induced by inflammatory response.

Results: Through the renal CaP deposition rat model established by UUO surgery combined with a high-calcium diet, UUO-induced inflammation was found to exacerbate calcium deposition induced by the high-calcium diet and significantly increased the renal expression of osteogenesis-related proteins including ALP, OPN, and Runx2. Both High-calcium and pro-inflammatory cytokines upregulated the expression of osteogenesis-related proteins such as OPN, OPG, and ALP, which was consistent with animal experiments. We further investigated whether pro-inflammatory cytokines promoted osteogenesis through their downstream MAPK pathway. We found that the blockage of the MAPK pathway by the inhibitors attenuated the levels of osteogenesis-related proteins induced by inflammation, indicating that cytokines triggered osteogenesis through the MAPK pathway.

Conclusion: The significance of this study lies in unveiling the mechanisms underlying the formation of CaP stones. Inflammation accelerated renal calcification by upregulating the osteogenesis-related proteins through the MAPK signaling pathway. In addition, our research established an appropriate and short-term animal model of renal interstitial CaP deposition, benefiting research for various kidney diseases.