Lithium Associated Tubulo-Interstitial Nephropathy (LATIN): role of collecting duct cells proliferation – LATIN

Bipolar disorder is a common condition, affecting 1 to 4% of the population worldwide, and a serious illness because of the suicidal risk during depressive and manic episodes. The most effective treatment to date is Lithium Carbonate. This undisputed efficacy is counterbalanced by long-term side effects, particularly renal effects. Among them nephrogenic diabetes insipidus occurs early during the treatment, while chronic kidney disease with renal microcysts is more progressive and may eventually lead to end-stage kidney disease. The pathophysiology of lithium-induced renal effects is reported to involve principal and intercalated cells of the collecting duct. Our preliminary results in a murine model exposed to therapeutic doses of lithium showed tubular dilatations and proliferation of both principal and intercalated cells. This proliferation was associated with morphological alteration of the primary cilium of the principal cells, an organelle essential for maintaining cell polarity and homeostasis. These ciliary alterations are comparable to other renal cystic pathologies such as polycystic kidney disease. This proliferation appears to be mediated by GDF15, a growth factor previously known in the laboratory for its proliferative effect on intercalated cells during acidosis. Our project aims to determine in vitro (including on 3D spheroids) and in vivo on a long-term exposure model (up to 6 months) the role and mechanisms of proliferation in the progression to microcysts and renal failure. The predictive value of the factors involved in this proliferation (including GDF15 but also by a hypothesis-free approach based on single cell urinary transcriptomics) will be evaluated in a cohort of patients treated with lithium. Finally, we will test in vitro and in vivo the preventive and/or curative effect of pharmacological inhibition of the action of GDF15 on diabetes insipidus, tubular proliferation, microcystic dilations and renal damage.