The single-cell landscape of kidney immune cells reveals transcriptional heterogeneity in early diabetic kidney disease

Fu, Jia; Sun, Zeguo; Wang, Xuan; Zhang, Tuo; Yuan, Weijie; Salem, Fadi; Yu, Sherry H.; Zhang, Weijia; Lee, Kyung Hwa; He, John Cijiang

doi:10.1016/j.kint.2022.08.026

Cited by 54 publications

(38 citation statements)

References 62 publications

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“…Of note, several of the genes (i.e. Trem2, Igf1, Gas6 ) and pathways (lysosome, endocytosis, regulation of apoptotic cell processes) enriched in Mrc1 + KRM overlapped with signatures previously assigned to Trem2 + macrophages, a cell type that is believed to restrict disease progression in several tissues including the kidney ( 46 – 48 ).…”

Section: Resultsmentioning

confidence: 86%

Cx3cr1 controls kidney resident macrophage heterogeneity

et al. 2023

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Kidney macrophages are comprised of both monocyte-derived and tissue resident populations; however, the heterogeneity of kidney macrophages and factors that regulate their heterogeneity are poorly understood. Herein, we performed single cell RNA sequencing (scRNAseq), fate mapping, and parabiosis to define the cellular heterogeneity of kidney macrophages in healthy mice. Our data indicate that healthy mouse kidneys contain four major subsets of monocytes and two major subsets of kidney resident macrophages (KRM) including a population with enriched Ccr2 expression, suggesting monocyte origin. Surprisingly, fate mapping data using the newly developed Ms4a3Cre Rosa Stopf/f TdT model indicate that less than 50% of Ccr2+ KRM are derived from Ly6chi monocytes. Instead, we find that Ccr2 expression in KRM reflects their spatial distribution as this cell population is almost exclusively found in the kidney cortex. We also identified Cx3cr1 as a gene that governs cortex specific accumulation of Ccr2+ KRM and show that loss of Ccr2+ KRM reduces the severity of cystic kidney disease in a mouse model where cysts are mainly localized to the kidney cortex. Collectively, our data indicate that Cx3cr1 regulates KRM heterogeneity and niche-specific disease progression.

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Section: Resultsmentioning

confidence: 86%

Cx3cr1 controls kidney resident macrophage heterogeneity

et al. 2023

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“…In another recently published mouse kidney scRNAseq data set, which contains all major kidney cell subtypes but without significant representation of glomerular cells ( 19 ), Tyro3 expression was absent in nonglomerular cells, while Mer was broadly expressed and Axl was expressed in kidney macrophages ( Supplemental Figure 1B ). We further examined an scRNAseq data set of CD45-enriched kidney immune cells ( 20 ), which similarly showed minimal expression of Tyro3, but varying degrees of expression of Mer and Axl in immune cell subsets ( Supplemental Figure 1C ). We also examined the expression of TYRO3 in human kidneys using the single-nucleus RNAseq data sets of control subjects and DKD patients ( http://humphreyslab.com/SingleCell ) ( 21 ).…”

Section: Resultsmentioning

confidence: 99%

“…S1B). We further examined a scRNAseq dataset of CD45-enriched kidney immune cells (20), which similarly showed a minimal expression of Tyro3, but varying degrees of expression of Mer and Axl in immune cell subsets (Fig. S1C).…”

Section: Tyro3 Expression Is Found Almost Exclusively In Podocytes Of...mentioning

confidence: 99%

TYRO3 agonist as therapy for glomerular disease

Zhong

Cai

et al. 2023

JCI Insight

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Podocyte injury and loss are key drivers of primary and secondary glomerular diseases, such as focal segmental glomerulosclerosis (FSGS) and diabetic kidney disease (DKD). We previously demonstrated the renoprotective role of protein S (PS) and its cognate tyrosine-protein kinase receptor, TYRO3, in models of FSGS and DKD and that their signaling exerts anti-apoptotic and anti-inflammatory effects to confer protection against podocyte loss. Among the three TAM receptors (TYRO3, AXL, and MER), only TYRO3 expression is largely restricted to podocytes, and glomerular TYRO3 mRNA expression negatively correlates with human glomerular disease progression. We, therefore, posited that the agonism PS-TYRO3 signaling could serve as a potential therapeutic approach to attenuate glomerular disease progression. As PS function is not limited to TYRO3-mediated signal transduction but includes its anticoagulant activity, we focused on the development of TYRO3 agonist as an optimal therapeutic approach to glomerular disease. Among the small molecule TYRO3 agonist compounds screened, compound-10 (C-10) showed a select activation of TYRO3 without any effects on AXL or MER. We also confirmed that C-10 directly binds to TYRO3, but not the other receptors. In vivo, C-10 attenuated proteinuria, glomerular injury, and podocyte loss in mouse models of adriamycin-induced nephropathy and db/db model of type 2 diabetes. Moreover, these renoprotective effects of C-10 are lost in Tyro3 knockout mice, indicating that C-10 is a select agonist of TYRO3 activity that mitigates podocyte injury and glomerular disease. Therefore, C-10, a novel TYRO3 agonist, could be potentially developed as a new therapy for glomerular disease.

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“…28 The burgeoning single-cell RNA-sequencing technologies enable the more precise identification of macrophage populations outside the conventional M1/M2 classification. 29,30 However, it should be noted that the in-depth understanding of the different macrophage phenotypes in DN remains to be elucidated by using more precise research methodology. The diverse origins, transcriptional complexity and sophisticated phenotypic switching of macrophages make it still difficult to accurately define macrophages subtypes and distinguish their functions, especially in the biological development of human macrophages.…”

Section: Origins and Phenotypes Of Macrophagesmentioning

confidence: 99%

“…The burgeoning single‐cell RNA‐sequencing technologies enable the more precise identification of macrophage populations outside the conventional M1/M2 classification 29,30 . However, it should be noted that the in‐depth understanding of the different macrophage phenotypes in DN remains to be elucidated by using more precise research methodology.…”

Section: Macrophagesmentioning

confidence: 99%

Innate immunity in diabetic nephropathy: Pathogenic mechanisms and therapeutic targets

Chen,

Lu,

et al. 2024

MedComm – Future Medicine

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Diabetic nephropathy (DN) represents a prevalent chronic microvascular complication of diabetes mellitus (DM) and is a major cause of end‐stage renal disease. The anfractuous surrounding of DN pathogenesis and the intricate nature of this metabolic disorder often pose challenges in both the diagnosis and treatment of DN compared to other kidney diseases. Hyperglycaemia in DM predispose vulnerable renal cells into microenvironmental disequilibrium and thereby results in innate immunocytes infiltration including neutrophils, macrophages, myeloid‐derived suppressor cells, dendritic cells, and so forth. These immune cells play dual roles in kidney injury and closely correlated with the degree of proteinuria in DN patients. Additionally, innate immune signaling cascades, initiated by altered metabolic and hemodynamic in diabetic context, are crucial in instigating and perpetuating renal inflammation, which detrimentally contribute to DN pathogenesis. As such, anti‐inflammatory therapies, particularly those targeting innate immunity, hold renoprotective promise in DN. In this article, we reviewed the origin and feature of the above four prominent kidney innate immune cells, analyze their pathogenic role in DN, and discuss potential targeted‐therapeutic strategies, aiming to enhance the current understanding of renal innate immunity and hence help to discover promising therapeutic approaches for DN.

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The single-cell landscape of kidney immune cells reveals transcriptional heterogeneity in early diabetic kidney disease

Cited by 54 publications

References 62 publications

Cx3cr1 controls kidney resident macrophage heterogeneity

Cx3cr1 controls kidney resident macrophage heterogeneity

TYRO3 agonist as therapy for glomerular disease

Innate immunity in diabetic nephropathy: Pathogenic mechanisms and therapeutic targets

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