131. Role of inflammatory induced TPO and thrombocytosis on kidney remodeling in Rapidly progressive glomerulonephritis
Creators: name: Mélodie Douté1, 2
name: Antonino Nicoletti1, 2
name: Caligiuri1, Giuseppina
name: Clément1, Marc
Publisher: name: Zenodo
Year: 2022
Subjects: Vasculitis
ANCA
Abstracts
Giant Cell Arthritis
MPA
GPA
EGPA
Takayasu
IgA vasculitis

description: <strong>Background:</strong> Rapidly progressive glomerulonephritis (RPGN) is a severe pathology induced by chronic inflammation of glomerular capillaries and driving glomerulosclerosis. This leads to rapid loss of kidney functions and drive renal failure (PMID:3287904). Current treatments (high-dose of corticosteroids) are associated with high morbi-mortality and poor prognosis. So, better insights into the pathophysiology of the RPGN are needed to unravel new therapeutic strategies. Platelets are known to be involved in the acute phase of inflammatory RPGN induced by auto-antibodies (PMID:16709860) but little is known about their contribution to glomerulosclerosis. Platelet production is mediated by thrombopoietin (TPO), which regulates megakaryocyte expansion in the bone marrow and platelet release in the blood stream (PMID:27358871). Interestingly, it is known that pro-inflammatory cytokines, such as IL6, can contribute to TPO production (PMID:11675343). Our hypothesis is that local kidney inflammation during RPGN induces TPO production, which overstimulates megakaryopoiesis, promotes glomerulosclerosis through platelets and worsen RPGN. <strong>Method:</strong> We used a mouse model of RPGN induced by a nephrotoxic serum (NTS) containing anti-glomerular basement membrane (anti-GBM) antibodies to reproduce the human disease. Systematic analysis of platelet count showed that NTS-injected mice developed a thrombocytosis compared to non-immune serum injected mice (control mice). Using a multiplex bead-based assay, we observed an increase of multiple hematopoietic growth factors in the plasma of NTS-injected mice. TPO concentration steadily increased over 7 days, as compared to control mice. Immunofluorescent staining and mRNA analysis in tissue lysate revealed a kidney specific TPO production following the injury, which was not observed in the liver or lungs. Albumin-creatinine ratio (ACR) measurement in urine and histological analysis revealed that thrombocytosis induction was correlated to albuminuria and renal fibrosis in NTS-injected mice. To get a better insight on inflammation induced TPO, thrombocytosis and RPGN progression we treated mice with immunosuppressive drugs (dexamethasone). This treatment inhibited the NTS-dependent thrombocytosis, plasmatic TPO elevation and drastically reduced renal fibrosis, in NTS-injected mice. To know if IL6 is involved in TPO production during RPGN, we neutralized the cytokine using an anti-IL6. This treatment only mildly reduced NTS-dependent thrombocytosis, failed to prevent TPO increase in plasma and had no impact on renal fibrosis and ACR in urine. This suggest that inflammation is a key process in TPO production and kidney remodeling during RPGN. However, TPO production and kidney fibrosis are not only IL6-dependent in this model, suggesting that other mediators are involved. Finally, to determine the role of platelets in RPGN, we depleted them using a neutralizing antibody (R300) in NTS-injected mice. Platelet depletion significantly reduced NTS-induced increase in ACR and prevented glomerulosclerosis, suggesting that platelets are involved in glomerulosclerosis, however platelet depleting therapeutic approach is not suitable for human disease. <strong>Conclusion:</strong> Altogether, our data suggest that in RPGN, local inflammation increases renal production of TPO which stimulates megakaryocyte’s expansion and NTS-dependent thrombocytosis, which contribute to glomerulosclerosis. Perspectives: We will investigate which inflammatory mediators contribute to TPO production in RPGN and how platelets contribute to fibrosis, potentially via growth factors, as TGFβ and PDGF, stored in alpha granules and released upon activation. This work could lead to the development of new potential therapeutic strategies targeting thrombocytosis to prevent RPGN progression. <strong>Disclosures</strong>: None