Role of GDF15 in Lithium-Induced Tubulointerstitial Remodeling

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Background: Lithium salts are the first-line treatment for bipolar disorder, a common and severe psychiatric condition. However, long-term use can cause two renal side effects: nephrogenic diabetes insipidus (NDI) and chronic microcystic tubulointerstitial nephropathy. The latter involves collecting duct remodeling, with increased cell proliferation and expansion of type A intercalated cells (A-ICs). GDF15 (Growth Differentiation Factor 15) is induced by vasopressin (AVP) and promotes A-IC proliferation in acidosis. We hypothesized that GDF15 may link lithium-induced NDI and nephropathy. Methods: In wild-type mice, we compared lithium chloride (LiCl)-treated and control groups. We measured GDF15 levels in plasma and urine (ELISA), and renal expression (qPCR). We assessed the correlation between GDF15 levels and renal phenotype, defined by polyuria and collecting duct remodeling. Remodeling was assessed by histology and machine learning analysis. We then studied the effect of GDF15 knockout on renal phenotype in a lithium-exposed mouse model. We also tested whether blocking the AVP V2 receptor (V2R) reduces LiCl-induced GDF15 expression and tubular remodeling. In parallel, we analyzed data from 200 lithium-treated patients, correlating urinary GDF15 with renal phenotype. Results: LiCl increased GDF15 levels in blood, urine, and kidney (Fig1). GDF15 levels correlated with polyuria and tubular changes. GDF15 knockout protected against both (Fig2). The effect of V2R inhibition on GDF15 and remodeling is under investigation. In patients, urinary GDF15 also correlated with renal phenotype. Conclusion: These findings support a potential contributory role of GDF15 in lithium-induced nephropathy. Ongoing spatial transcriptomic analysis in a lithium-exposed mouse model will help refine our understanding of the underlying mechanisms. Funding: Government Support – Non-U.S.

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