GATA6 marks fibrosis-associated stromal cells rather than repair macrophages in kidney disease

The mechanisms underlying kidney repair remain incompletely understood. GATA6-expressing large cavity macrophages are reported to facilitate inflammation resolution and repair in several organs following injury, but their role in kidney disease is unknown. GATA6 expression was minimal in normal mouse and human kidney. Across three experimental kidney disease models (ischemia-reperfusion injury, unilateral ureteric obstruction and nephrotoxic serum glomerulonephritis), GATA6 expression increased progressively in the renal interstitium with chronic, but not acute injury. Immunophenotyping demonstrated that GATA6 + cells mainly expressed stromal markers (RGS4, PDGFRβ, αSMA) as opposed to leukocyte markers (CD45, F4/80, MHC-II). Single-cell RNA sequencing confirmed enrichment of Gata6 expression in kidney stromal cell populations. GATA6 + cells expressed genes associated with stromal cell identity, repair, inflammation, angiogenesis and collagen biosynthesis. In human kidney biopsies from patients with hypertensive nephrosclerosis and IgA nephropathy, interstitial GATA6 expression was increased and correlated with the degree of fibrosis. As in mice, human GATA6 + cells were largely CD45 and MHC-II negative but expressed stromal markers, consistent with non-immune interstitial cells rather than macrophages. Together, these findings demonstrate that GATA6 is predominantly expressed by kidney stromal cells with limited evidence of a major role for GATA6 + large cavity macrophages in kidney injury and repair.