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Background <p>Local interstitial acidosis in chronic kidney disease (CKD) induces inflammatory responses and dedifferentiation of proximal tubule cells (PTCs), disrupting cellular crosstalk through cytokine and COX-2 metabolite secretion. This promotes a switch to an inflammatory fibroblast phenotype, further exacerbating inflammation and PTC dedifferentiation. p38-signaling and downstream transcription factors, including P-CREB and c-fos, contribute to these responses. This study investigates the impact of acidosis on inflammatory responses in PTCs and fibroblasts, focusing on cellular crosstalk and the role of p38-signaling.</p> Methods <p>HK-2 (human PTCs) and CCD-1092Sk (human fibroblasts) were exposed to acidic or control media in mono- and coculture for 30&#xa0;min, 3&#xa0;h, or 48&#xa0;h. Protein expression of IL-6, phosphorylated (P-) and total CREB, P- and total SRF, c-fos, and P- and total p38 was analyzed by western blot. IL-6 secretion was measured using ELISA. The impact of p38 and IL-6 receptor activity was assessed by pharmacological intervention.</p> Results <p>In coculture, acidosis initially caused a transient decrease in IL-6 secretion but significantly increased IL-6 levels after 48&#xa0;h. Acidosis induced intracellular IL-6 expression in HK-2 cells within 3&#xa0;h independent of culture conditions, with sustained IL-6 protein increase after 48&#xa0;h only in coculture. Acidosis also enhanced P-CREB and c-fos expression in coculture during the first 3&#xa0;h. Regardless of culture conditions, acidosis increased IL-6, c-fos, and P-SRF expression in CCDSK cells after 48&#xa0;h. P-CREB and COX-2 expression were elevated in CCDSK in coculture. Acidosis-mediated effects on IL-6, P-CREB, and P-SRF expression were p38-dependent in both cell lines. Finally, we assessed the pH-dependency of IL-6 action and found that IL-6 addition increased COX-2 expression via the IL-6 receptor in acidic but not control media. Thus, acidosis enhances IL-6 secretion and potentiates its receptor-mediated biological effects.</p> Conclusion <p>This study identifies IL-6 as a key mediator of tubule-fibroblast crosstalk in an acidic milieu, promoting inflammatory processes. Acidosis induces IL-6 expression, secretion, and biological effects, with p38 kinase as a crucial mediator. If validated in vivo, these findings could enhance understanding of CKD and support early interventions.</p>

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Acidosis-induced p38-kinase activation triggers an IL-6-mediated crosstalk of renal proximal tubule cells with fibroblasts leading to their inflammatory response

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月11日

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  • Marie-Christin Schulz,
  • Nathalie Wolff,
  • Michael Kopf,
  • Micheal Gekle

摘要

Background

Local interstitial acidosis in chronic kidney disease (CKD) induces inflammatory responses and dedifferentiation of proximal tubule cells (PTCs), disrupting cellular crosstalk through cytokine and COX-2 metabolite secretion. This promotes a switch to an inflammatory fibroblast phenotype, further exacerbating inflammation and PTC dedifferentiation. p38-signaling and downstream transcription factors, including P-CREB and c-fos, contribute to these responses. This study investigates the impact of acidosis on inflammatory responses in PTCs and fibroblasts, focusing on cellular crosstalk and the role of p38-signaling.

Methods

HK-2 (human PTCs) and CCD-1092Sk (human fibroblasts) were exposed to acidic or control media in mono- and coculture for 30 min, 3 h, or 48 h. Protein expression of IL-6, phosphorylated (P-) and total CREB, P- and total SRF, c-fos, and P- and total p38 was analyzed by western blot. IL-6 secretion was measured using ELISA. The impact of p38 and IL-6 receptor activity was assessed by pharmacological intervention.

Results

In coculture, acidosis initially caused a transient decrease in IL-6 secretion but significantly increased IL-6 levels after 48 h. Acidosis induced intracellular IL-6 expression in HK-2 cells within 3 h independent of culture conditions, with sustained IL-6 protein increase after 48 h only in coculture. Acidosis also enhanced P-CREB and c-fos expression in coculture during the first 3 h. Regardless of culture conditions, acidosis increased IL-6, c-fos, and P-SRF expression in CCDSK cells after 48 h. P-CREB and COX-2 expression were elevated in CCDSK in coculture. Acidosis-mediated effects on IL-6, P-CREB, and P-SRF expression were p38-dependent in both cell lines. Finally, we assessed the pH-dependency of IL-6 action and found that IL-6 addition increased COX-2 expression via the IL-6 receptor in acidic but not control media. Thus, acidosis enhances IL-6 secretion and potentiates its receptor-mediated biological effects.

Conclusion

This study identifies IL-6 as a key mediator of tubule-fibroblast crosstalk in an acidic milieu, promoting inflammatory processes. Acidosis induces IL-6 expression, secretion, and biological effects, with p38 kinase as a crucial mediator. If validated in vivo, these findings could enhance understanding of CKD and support early interventions.