The roles of hyaluronan in kidney development, physiology and disease

The hyaluronan (HA) matrix in the tissue microenvironment is crucial for maintaining homeostasis by regulating inflammatory signalling, endothelial-mesenchymal transition and cell migration. During development, covalent modifications and osmotic swelling of HA create mechanical forces that initiate midgut rotation, vascular patterning and branching morphogenesis. Together with its main cell surface receptor, CD44, HA establishes a physicochemical scaffold at the cell surface that facilitates the interaction and clustering of growth factors and receptors that is required for normal physiology. High-molecular-weight HA, tumour necrosis factor-stimulated gene 6, pentraxin 3 and CD44 form a stable pericellular matrix that promotes tissue regeneration and reduces inflammation. By contrast, breakdown of high-molecular-weight HA into depolymerized fragments by hyaluronidases triggers inflammatory signalling, leukocyte migration and angiogenesis, contributing to tissue damage and fibrosis in kidney disease. Targeting HA metabolism is challenging owing to its dynamic regulation and tissue-specific functions. Nonetheless, modulating HA matrix functions by targeting its binding partners holds promise as a therapeutic strategy for restoring tissue homeostasis and mitigating pathological processes. Further research in this area is warranted to enable the development of novel therapeutic approaches for kidney and other diseases characterized by dysregulated HA metabolism. Hyaluronan is a critical component of the extracellular matrix, with key roles in tissue homeostasis, cellular signalling and immune responses. Here, the authors describe the roles of hyaluronan in kidney development, adult kidney physiology and kidney disease. Hyaluronan (HA) is a key component of the extracellular matrix that has critical roles in tissue homeostasis, organogenesis, cell signalling, cell migration and regulation of immune responses.Together with its cell surface receptor CD44 and HA-binding proteins such as TSG6 and pentraxin3, high-molecular-weight (HMW)-HA creates a stable pericellular matrix that facilitates tissue regeneration and reduces inflammation.Depolymerization of HMW-HA enables tissue remodelling and generates HA fragments that can activate inflammatory signalling, recruit leukocytes and promote angiogenesis.During development, covalent modifications and osmotic swelling of HA create mechanical forces that initiate midgut rotation, vascular patterning and branching morphogenesis.In kidney injury and disease, synthesis of HMW-HA contributes to tissue regeneration, whereas dysregulated breakdown of HA has been associated with inflammation, hyalinosis and fibrosis; in renal cell carcinoma, high tumour levels of HA are associated with an unfavourable prognosis.HA metabolism is an unlikely therapeutic target owing to its dynamic, tissue-specific regulation and fundamental importance for tissue homeostasis; however, HA binding partners could potentially be targeted to modulate HA matrix functions and mitigate pathological processes in kidney disease.