Accumulation of Ultra-Low Molecular Weight Hyaluronan After Kidney Injury Drives AKI-to-CKD Transition via Lymphangiogenesis

Background: Hyaluronan (HA) is a disaccharide unit glycosaminoglycan composed of D-glucuronide and N-acetylglucosamine in the extracellular matrix. Its receptor is mainly located in lymphatic endothelial cells (LECs), and its degraded fragment ultra-low molecular weight hyaluronan (ULMWHA) has been reported as one of the survivor factors for lymphangiogenesis, which is supposed involving in the progression of chronic kidney disease (CKD). However, the role of ULMWHA-regulated lymphangiogenesis in CKD has not be explored. Methods: We analyzed the association between hyaluronan, lymphangiogenesis, and kidney injury in human renal biopsy specimens. Via ischemia-reperfusion injury (IRI) model in mice, we detected renal lymphangiogenesis and injury phenotypes following administration of ULMHA, as well as the effects of receptor blockade. Complementary in vitro experiments and RNA-seq analyses revealed that LYVE1-ULMHA interaction induces morphological and viability changes in lymphatic endothelial cells (LECs), along with the underlying signaling pathways involved. Results: We found the deposition of HA in renal interstitium is associated with renal interstitial fibrosis and renal function decline in patients with CKD. Then, we demonstrated the main component of the accumulated HA in renal interstitium was ULMWHA with significant renal lymphangiogenesis after IRI in mice, while these lymphangiogenesis and the following renal injury, inflammation and fibrosis were abrogated by blocking the binding of ULMWHA to its receptor with a soluble LYVE-1 peptide or by knockdown of proliferative lymphatic vessels. The supplement of ULMWHA significantly increased proliferation and tube formation of LECs, and accelerated renal inflammation and renal fibrosis. Conclusion: The accumulated ULMWHA after IRI injury triggers intracellular signaling cascade through interaction with its receptor LYVE-1, thereby promote lymphangiogenesis, and the following renal inflammation and fibrosis. The ULMWHA driving lymphangiogenesis and the subsequent CKD provides a new insight in the development of novel therapeutic strategies to prevent progression of IRI-associated renal inflammation and fibrosis.