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Abstract: SA-PO1006

Renal Klotho Provides Inter-Organ Protection of Bone Marrow Hematopoiesis Against Phosphate Toxicity

Session Information

  • CKD: Pathobiology - II
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Yang, Ke, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
  • Du, Changhong, Institute of Combined Injury of PLA, Army Medical University (Third Military Medical University), Chongqing, China
Background

Hematopoietic disorders including arterial thrombosis, innate immune inflammation and adaptive immunodeficiency are prevalent in patients with chronic kidney disease (CKD). However, the pathogenetic mechanism and the interactions between kidneys and bone marrow (BM) hematopoiesis remain poorly understood.

Methods

The role of kidney and renal Klotho in the regulation of BM hematopoiesis were evaluated in vivo and ex vivo, and confirming in targeted gene knockout and kidney-specific knockout mice.

Results

We found that CKD was characterized by myeloid-biased hematopoiesis and renal Klotho deficiency contributed to myeloid bias in CKD via impairing BM hematopoietic stem cell (HSC) maintenance. Using kidney-specific Klotho deletion mice and a CKD mouse model, we revealed that kidney-secreted soluble Klotho maintained pool size and differentiation propensity of human and mouse HSCs in an inter-organ manner through regulating inorganic phosphate (Pi) homeostasis of HSCs. Mechanistically, soluble carrier family 20 member 1 (SLC20A1) mediated Pi absorption and diphosphoinositol pentakisphosphate kinase 2 (PPIP5K2) mediated Pi sensing and signal transduction to Akt in HSCs; whereas renal Klotho restrained SLC20A1-mediated Pi absorption of HSCs. Klotho/Pi perturbation-induced Pi toxicity in CKD and high Pi diet (HPD) hyperactivated SLC20A1-PPIP5K2-Akt pathway to self-amplify Pi toxicity and boost GATA2 and mitochondrial activities in HSCs, which promoted expansion and megakaryocyte/myeloid-biased differentiation of HSCs and ultimately megakaryocyte/myeloid-biased hematopoiesis. Furthermore, single-cell RNA-sequencing revealed a heterogenous Pi metabolic signature, which might underlie the distinct response of HSCs to Pi toxicity. Importantly, targeting Klotho/Pi-SLC20A1-PPIP5K2-Akt axis prevented Pi toxicity to BM hematopoiesis in CKD and HPD.

Conclusion

Our study uncovers a hitherto unrecognized role of kidneys in the regulation of BM HSC maintenance through secreting Klotho, and identifies that soluble Klotho and Pi are critical extrinsic factors that govern BM HSC maintenance. The findings not only provide deep insight into the function and composition of BM niches, but also extend our understanding of inter-organ regulation of BM hematopoiesis. Targeting Klotho/Pi-SLC20A1-PPIP5K2-Akt axis holds promise in protecting BM hematopoiesis against Pi toxicity such as in CKD and HPD.

Funding

  • Government Support – Non-U.S.