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Credit: Lara Crow/Springer Nature Limited in the glomerulus, parietal epithelial cells (PeCs) are well known for their contribution, along with podocytes, to sclerotic lesions in primary focal and segmental glomerulonephritis (FsGs). Now, Kuppe, Moeller and colleagues report that parietal cells with features of proximal tubular cells (PtCs) might “represent a hotspot for lesion formation in the early stages of glomerular disease.” in response to injury, PtCs can transiently activate a scattered tubular cell (stC) transcriptional programme that enhances cellular activation and proliferation; this response is thought to contribute to tubular cell regeneration. in human kidney biopsy samples, in addition to the classical flat PeCs that line the Bowman’s capsule, the researchers identified a group of PeCs at the PeC–PtC border that co-expressed keratin 7 and 19, two stC phenotype markers — these cells were termed intermediate PeCs (iPeCs). in some glomeruli, PtC-like cells, termed cuboidal PeCs, extended from the proximal tubule into the Bowman’s capsule. in mice, expression of the stC marker cyclin D1 identified iPeCs, which were located between flat and cuboidal PeCs near the proximal tubule. the researchers used transgenic mice to fluorescently label either all PeCs, or only cuboidal PeCs and iPeCs, for lineage tracing studies. “in ageing mice, we found no evidence that flat PeCs regenerate cuboidal PeCs or vice versa, which argues against previous reports of a potential progenitor niche at this location,” remarks Moeller. Following FsGs induction in thy1.1 mice, cuboidal PeCs and iPeCs expressed the highest levels of proliferation and activation markers in the glomerulus. Moreover, in the 5/6 nephrectomy and DOCa/salt model of FsGs, both sclerotic and proliferative lesions contained PtC-like cells (that is, cuboidal PeCs and iPeCs). Finally, in human renal biopsy samples of early FsGs recurrences, cells that expressed keratin 7, a marker found in human iPeCs, were particularly abundant in tip lesions, in which adhesions are formed near the tubular pole. “Our findings in mice and humans demonstrate that tip lesions originate from iPeCs,” concludes Kuppe. “we plan to investigate what promotes the migration of proximal tubule cells into the Bowman’s capsule and whether the presence of these cells is a risk factor for renal lesion formation,” explains Moeller. Monica Wang g lO M e r U lO n e P H r i t i S