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Renal development is a complex process in which two major processes, tubular branching and nephron development, regulate each other reciprocally. Our previous findings have indicated that collagen XVIII (ColXVIII), an extracellular matrix protein, affects the renal branching morphogenesis. We investigate here the role of ColXVIII in nephron formation and the behavior of nephron progenitor cells (NPCs) using isoform-specific ColXVIII knockout mice. The results show that the short ColXVIII isoform predominates in the early epithelialized nephron structures whereas the two longer isoforms are expressed only in the later phases of glomerular formation. Meanwhile, electron microscopy showed that the ColXVIII mutant embryonic kidneys have ultrastructural defects at least from embryonic day 16.5 onwards. Similar structural defects had previously been observed in adult ColXVIII-deficient mice, indicating a congenital origin. The lack of ColXVIII led to a reduced NPC population in which changes in NPC proliferation and maintenance and in macrophage influx were perceived to play a role. The changes in NPC behavior in turn led to notably reduced overall nephron formation. In conclusion, the results show that ColXVIII has multiple roles in renal development, both in ureteric branching and in NPC behavior., Competing Interests: Declaration of competing interest There are no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Collagen XVIII (ColXVIII) is a component of the extracellular matrix implicated in embryogenesis and control of tissue homoeostasis. We now provide evidence that ColXVIII has a specific role in renal branching morphogenesis as observed in analyses of total and isoform-specific knockout embryos and mice. The expression of the short and the two longer isoforms differ temporally and spatially during renal development. The lack of ColXVIII or its specific isoforms lead to congenital defects in the 3D patterning of the ureteric tree where the short isoform plays a prominent role. Moreover, the ex vivo data suggests that ColXVIII is involved in the kidney epithelial tree patterning via its N-terminal domains, and especially the Thrombospondin-1-like domain common to all isoforms. This morphogenetic function likely involves integrins expressed in the ureteric epithelium. Altogether, the results point to an important role for ColXVIII in the matrix-integrin-mediated functions regulating renal development., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Endostatin (EST), an antiangiogenic factor, is enriched in aging kidneys. EST is also an interactive partner of transglutaminase 2 (TG2), an enzyme that cross-links extracellular matrix proteins. Here we tested whether EST and TG2 play a role in the fibrosis of aging. In wild-type mice, aging kidneys exhibited a 2- to 4-fold increase in TG2 paralleled by increased cross-linked extracellular matrix proteins and fibrosis. Mice transgenic to express EST showed renal fibrosis at a young age. One-month delivery of EST via minipumps to young mice showed increased renal fibrosis that became more robust when superimposed on folic acid-induced nephropathy. Upregulated TG2 and impaired renal function were apparent with EST delivery combined with folic acid-induced nephropathy. Subcapsular injection of TG2 and/or EST into kidneys of young mice not only induced interstitial fibrosis, but also increased the proportion of senescent cells. Thus, kidney fibrosis in aging may represent a natural outcome of upregulated EST and TG2, but more likely it appears to be a result of cumulative stresses occurring on the background of synergistically acting geronic (aging) proteins, EST and TG2., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)