A kidney resident macrophage subset is a candidate biomarker for renal cystic disease in preclinical models

Li, Zhang; Zimmerman, Kurt A.; Cherakara, Sreelakshmi; Chumley, Phillip; Collawn, James F.; Wang, Jun; Haycraft, Courtney J.; Song, Chun-Yan; Chacana, Teresa; Andersen, Reagan S; Croyle, Mandy J.; Aloria, Ernald J; Hombal, Raksha P; Thomas, Isis N; Chweih, Hanan; Simanyi, Kristin L; George, James F.; Parant, John M.; Mrug, Michal; Yoder, Bradley K.

doi:10.1242/dmm.049810

Cited by 8 publications

(7 citation statements)

References 42 publications

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“…This response may be impaired, as evidenced by reduction in VEGFR expression in pericystic endothelium, a finding also reflected by previous work showing loss of VEGF signalling as a feature of PKD rodent models (29, 89). Alternatively pericystic endothelium, in its altered phenotypic state, could contribute to further inflammation and fibrotic remodelling, by driving the recruitment and activation of adjacent cells, including fibroblasts (17) or macrophages (90, 91). In any case, these vessels are associated with a decline in local cortical perfusion within the kidney, as we demonstrated using ASL of Pkd1 RC/RC mouse kidneys at the early, 3-month stage of the disease.…”

Section: Discussionmentioning

confidence: 99%

A unique subset of pericystic endothelium associates with aberrant microvascular remodelling and impaired blood perfusion early in polycystic kidney disease

Jafree,

Perera,

Ball

et al. 2024

Preprint

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Hallmarks of autosomal dominant polycystic kidney disease (ADPKD), the most common hereditary kidney anomaly, include expanding fluid-filled epithelial cysts, inflammation, and fibrosis. Despite previous work showing the potential of vascular-based therapies, renal microvascular alterations in ADPKD, and their timing, are poorly understood. Using single-cell transcriptomics of human kidney microvasculature, we identify a population of endothelial cells adjacent to cysts in ADPKD. This pericystic endothelium, distinguishable by its expression of osteopontin (SPP1), has a distinct molecular profile compared to the common endothelial cell injury signature in other kidney diseases. SPP1+ pericystic endothelium was also present in an orthologous mouse model of ADPKD before overt kidney functional decline. By interrogating geometric, topological and fractal properties from three-dimensional imaging of early ADPKD mouse kidneys, we show that pericystic endothelium associates with disorganisation and non-uniformity of the renal cortical microvasculature. Concurrently, we detected region-specific reductions in cortical blood flow within ADPKD murine kidneys using arterial spin labelling. We conclude that ADPKD kidneys contain a unique subset of endothelium manifesting with aberrant remodelling and impaired blood perfusion. Its detection, prior to renal functional decline, advocates the vasculature as a therapeutic target to modulate or preserve renal function in early ADPKD.

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Section: Discussionmentioning

confidence: 99%

A unique subset of pericystic endothelium associates with aberrant microvascular remodelling and impaired blood perfusion early in polycystic kidney disease

Jafree,

Perera,

Ball

et al. 2024

Preprint

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“…CD45 + renal leukocytes were selected, while granulocytes (using Ly6G staining) and CD11B – cells were excluded. Gating was then set to distinguish between F4/80 – (early infiltrating monocytes), F4/80 int (BM-derived renal macrophages), and F4/80 hi (kidney-resident macrophages [KRM]) cells, as described ( Supplemental Figure 13 ) ( 67 , 69 ). There was an expected increase in total CD45 + , CD11B + , and CD45 + CD11B + nongranulocyte (ly6G – ) mononuclear cells after IRI-AKI, there was no difference in total cell numbers between PEPCK Cre + and Cre – kidneys ( Supplemental Figure 14 ).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of retinoic acid signaling in proximal tubular epithelial cells protects against acute kidney injury

Yang,

Lopez,

Brewer

et al. 2023

JCI Insight

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PTECs that have phagocytosed apoptotic cells (27). However, in other settings, overexpression of Kim1 may provoke inflammation and fibrosis. For example, a conditional mouse mutant that induces persistent Kim1 expression in renal epithelium provokes renal inflammation and fibrosis in adult mice (30). In addition, persistent Kim1 expression is a feature of inflammatory PTECs that have failed to undergo productive repair after AKI (10,31,32). On this basis, it is unclear whether enhancing Kim1 expression after AKI would be protective or would cause more severe injury and CKD.The retinoic acid (RA) signaling plays an essential role in mammalian kidney development ( 33), but in the adult kidney, RA signaling is restricted to occasional cells within the collecting duct (CD) system (34). RA metabolites are generated in a 2-step process that includes the rate-limiting oxidation of retinaldehyde to RA by retinaldehyde dehydrogenases (RALDHs, encoded by the ALDH1A gene family). Once generated, RAs may act in an autocrine or paracrine fashion and mediate effects by binding to the RA receptors (RARs), which activate or repress transcriptional targets to regulate diverse cellular functions. These effects are cell type and context dependent. For example, RA can promote epithelial differentiation in some circumstances, while in others, it enhances stem cell-like properties (35-37), and RAR signaling promotes heart, limb, and fin appendage regeneration in amphibia and fish (38)(39)(40).We have shown that Raldh2 and Raldh3 are induced in peritubular monocyte/macrophages and myofibroblasts after IRI-AKI and have used RAR reporter mice to show that RAR signaling is activated in adjacent renal macrophages and in injured Kim1 + PTECs after IRI-AKI (41). Systemic inhibition of RAR signaling worsens renal injury and increases inflammatory macrophage activation after IRI-AKI, and macrophage-depletion studies show that worsening injury after inhibition of RAR signaling is dependent on macrophages (41). These findings are consistent with the known antiinflammatory effects of RAR signaling in macrophages (42-46) and the protective effects of exogenous retinoids on renal injury in toxin and IRI-AKI models (41,47,48), in which RA treatments reduce both tubular injury and inflammation in the kidney (41, 47). However, these findings do not explain the functional role that activation of RAR signaling in PTECs plays in the cellular responses to injury, nor whether this response to injury is conserved in patients or in other experimental models of AKI.We now show that PTEC RAR signaling is activated in patients with SA-AKI and mice with Rhabdo-AKI, and we show that inhibition of RAR signaling in PTECs protects against Rhabdo-AKI and, to a lesser extent, IRI-AKI. This is associated with increased Kim1-dependent efferocytosis by PTECs. Increased Kim1 expression is not associated with increased tubular injury but is associated with enhanced dedifferentiation, proliferation, and metabolic reprogramming of PTECs. These findings provide the first gain...

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“…In this small group of ADPKD patients, baseline urinary CD14 levels (but not GFR) significantly correlated with a two-year rate of TKV change, indicating that urinary CD14 level could serve as a predictor of ADPKD outcome. Despite the strong correlations detected by flow cytometry analyses in these studies (93)(94)(95), the reported results are limited by small cohorts of ADPKD patients and, as a consequence, lack of the multiple covariate effects evaluation. Therefore, additional flow cytometry analyses in larger, well-characterized cohorts of ADPKD patients are required for validation of the reported findings and drawing conclusions.…”

Section: Urine Inflammatory Glomerular and Tubular Damage Biomarkersmentioning

confidence: 87%

“…Zimmerman et al (93) reported an increased total number of intrarenal CD4 and CD8 T cells and a correlation between urinary CD4+ T cell count and annual eGFR decline over 5 years in a small cohort of ADPKD patients (n = 30), suggesting this novel marker as a candidate prognostic biomarker in ADPKD and supporting the proposed role of T cells in ADPKD pathogenesis. Li et al (94) reported increased number of CD206 + macrophages in kidneys and urine from 30 ADPKD patients. The number of CD206 + macrophages correlated with the annual eGFR decline, indicating its utility for assessing disease activity and predicting renal function decline in ADPKD patients.…”

Section: Urine Inflammatory Glomerular and Tubular Damage Biomarkersmentioning

confidence: 99%

Predicting autosomal dominant polycystic kidney disease progression: review of promising Serum and urine biomarkers

Sorić Hosman,

Cvitković Roić,

Fištrek Prlić

et al. 2023

Front. Pediatr.

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Autosomal dominant polycystic kidney disease (ADPKD) is one of the leading causes of end-stage renal disease. In spite of the recent tremendous progress in the understanding of ADPKD pathogenesis, the molecular mechanisms of the disease remain incompletely understood. Considering emerging new targeted therapies for ADPKD, it has become crucial to disclose easily measurable and widely available biomarkers for identifying patients with future rapid disease progression. This review encompasses all the research with a shared goal of identifying promising serum or urine biomarkers for predicting ADPKD progression or response to therapy. The rate of the ADPKD progress varies significantly between patients. The phenotypic variability is only partly explained by the underlying genetic lesion diversity. Considering significant decline in kidney function in ADPKD is not usually evident until at least 50% of the parenchyma has been destroyed, conventional kidney function measures, such as glomerular filtration rate (GFR), are not suitable for monitoring disease progression in ADPKD, particularly in its early stages. Since polycystic kidney enlargement usually precedes the decline in GFR, height-adjusted total kidney volume (ht-TKV) has been accepted as an early biomarker for assessing disease severity in ADPKD patients. However, since measuring ht-TKV is time-consuming and observer-dependent, the identification of a sensitive and quickly measurable biomarker is of a great interest for everyday clinical practice. Throughout the last decade, due to development of proteomic and metabolomic techniques and the enlightenment of multiple molecular pathways involved in the ADPKD pathogenesis, a number of urine and serum protein biomarkers have been investigated in ADPKD patients, some of which seem worth of further exploring. These include copeptin, angiotensinogen, monocyte chemoattractant protein 1, kidney injury molecule-1 and urine-to-plasma urea ratio among many others. The aim of the current review is to provide an overview of all of the published evidence on potentially clinically valuable serum and urine biomarkers that could be used for predicting disease progression or response to therapy in patients with ADPKD. Hopefully, this review will encourage future longitudinal prospective clinical studies evaluating proposed biomarkers as prognostic tools to improve management and outcome of ADPKD patients in everyday clinical practice.

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A kidney resident macrophage subset is a candidate biomarker for renal cystic disease in preclinical models

Cited by 8 publications

References 42 publications

A unique subset of pericystic endothelium associates with aberrant microvascular remodelling and impaired blood perfusion early in polycystic kidney disease

A unique subset of pericystic endothelium associates with aberrant microvascular remodelling and impaired blood perfusion early in polycystic kidney disease

Inhibition of retinoic acid signaling in proximal tubular epithelial cells protects against acute kidney injury

Predicting autosomal dominant polycystic kidney disease progression: review of promising Serum and urine biomarkers

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