Abstract Understanding kidney disease relies on defining the complexity of cell types and states, their associated molecular profiles and interactions within tissue neighbourhoods 1 . Here we applied multiple single-cell and single-nucleus assays (&gt;400,000 nuclei or cells) and spatial imaging technologies to a broad spectrum of healthy reference kidneys (45 donors) and diseased kidneys (48 patients). This has provided a high-resolution cellular atlas of 51 main cell types, which include rare and previously undescribed cell populations. The multi-omic approach provides detailed transcriptomic profiles, regulatory factors and spatial localizations spanning the entire kidney. We also define 28 cellular states across nephron segments and interstitium that were altered in kidney injury, encompassing cycling, adaptive (successful or maladaptive repair), transitioning and degenerative states. Molecular signatures permitted the localization of these states within injury neighbourhoods using spatial transcriptomics, while large-scale 3D imaging analysis (around 1.2 million neighbourhoods) provided corresponding linkages to active immune responses. These analyses defined biological pathways that are relevant to injury time-course and niches, including signatures underlying epithelial repair that predicted maladaptive states associated with a decline in kidney function. This integrated multimodal spatial cell atlas of healthy and diseased human kidneys represents a comprehensive benchmark of cellular states, neighbourhoods, outcome-associated signatures and publicly available interactive visualizations. 

pdf/an-atlas-of-healthy-and-injured-cell-states-and-niches-in-2xssn61ams.pdf

An atlas of healthy and injured cell states and niches in the human kidney

The proportion of older people in the general population is steadily increasing worldwide, with the most rapid growth in low- and middle-income countries [1]. This demographic change is to be celebrated, because it is the consequence of socioeconomic development and better life expectancy. However, population aging also has important implications for society—in diverse areas including health systems, labor markets, public policy, social programs, and family dynamics [2]. A successful response to the aging population will require capitalizing on the opportunities that this transition offers, as well as effectively addressing its challenges.

Chronic kidney disease (CKD) is an important public health problem that is characterized by poor health outcomes and very high health care costs. CKD is a major risk multiplier in patients with diabetes, hypertension, heart disease and stroke—all of which are key causes of death and disability in older people [3]. Since the prevalence of CKD is higher in older people, the health impact of population aging will depend in part on how the kidney community responds. 

March 13, 2014 will mark the celebration of the 9th World Kidney Day (WKD), an annual event jointly sponsored by the International Society of Nephrology and the International Federation of Kidney Foundations. Since its inception in 2006, WKD has become the most successful effort to raise awareness among policymakers and the general public about the importance of kidney disease. The topic for WKD 2014 is “CKD in older people.” This article reviews the key links between kidney function, age, health and illness—and discusses the implications of the aging population for the care of people with CKD.

/pdf/chronic-kidney-disease-and-the-aging-population-3j8vya6gwj.pdf

Chronic kidney disease and the aging population.

Cilia are essential for the ontogeny and function of many tissues, including the kidney. In mammals, Esrr{gamma} has been previously established as a significant determinant of renal health, with decreased expression linked to age related dysfunction, cyst formation, and kidney disease. Here, we report that the Esrr{gamma} vertebrate ortholog estrogen related receptor gamma a (esrr{gamma}a) is essential for proper cell fate choice within kidney functional units (nephrons) as well as ciliogenesis. Deficiency of esrr{gamma}a resulted in nephrons with alterations in proximodistal segmentation and a decreased multiciliated epithelial cell populace. Surprisingly, esrr{gamma}a deficiency disrupted renal ciliogenesis and caused a similar abrogation within the developing node and otic vesicle--all defects that occurred independently of changes in cell polarity or basal body organization. These phenotypes were consistent with interruptions in prostaglandin signaling, and we found that ciliogenesis was rescued in esrr{gamma}a deficient embryos with exogenous PGE2 or through overexpression of the cyclooxygenase enzyme Ptgs1. Through genetic interaction studies, we found that peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (ppargc1a), which acts upstream of Ptgs1-mediated prostaglandin synthesis, has a synergistic relationship with esrr{gamma}a in the ciliogenic pathway. These data position esrr{gamma}a as a novel link between ciliogenesis and nephrogenesis through regulation of prostaglandin signaling and cooperation with ppargc1a, and highlight esrr{gamma}a as a potential new target for future ciliopathic treatments.

https://www.biorxiv.org/content/biorxiv/early/2021/11/19/2021.11.17.468871.full.pdf

Esrrγa regulates nephron development and ciliogenesis by controlling prostaglandin synthesis and cooperation with Ppargc1a

Many studies implicate mitochondrial dysfunction as a key contributor to cell loss in Parkinson disease (PD). Previous analyses of dopaminergic (DAergic) neurons from patients with Lewy-body pathology revealed a deficiency in nuclear-encoded genes for mitochondrial respiration, many of which are targets for the transcription factor estrogen-related receptor gamma (Esrrg/ERRγ). We demonstrate that deletion of ERRγ from DAergic neurons in adult mice was sufficient to cause a levodopa-responsive PD-like phenotype with reductions in mitochondrial gene expression and number, that partial deficiency of ERRγ hastens synuclein-mediated toxicity, and that ERRγ overexpression reduces inclusion load and delays synuclein-mediated cell loss. While ERRγ deletion did not fully recapitulate the transcriptional alterations observed in postmortem tissue, it caused reductions in genes involved in synaptic and mitochondrial function and autophagy. Altogether, these experiments suggest that ERRγ-deficient mice could provide a model for understanding the regulation of transcription in DAergic neurons and that amplifying ERRγ-mediated transcriptional programs should be considered as a strategy to promote DAergic maintenance in PD. 

/pdf/estrogen-related-receptor-gamma-regulates-mitochondrial-and-3sq40q0k.pdf

Estrogen-related receptor gamma regulates mitochondrial and synaptic genes and modulates vulnerability to synucleinopathy

Aging is a degenerative process that results from the accumulation of cellular and tissue lesions, leading progressively to organ dysfunction and death. Although the biological basis of human aging remains unclear, a large amount of data points to deregulated mitochondrial function as a central regulator of this process. Mounting years of research on aging support the notion that the engendered age-related decline of mitochondria is associated with alterations in key pathways that regulate mitochondrial biology. Particularly, several studies in the last decade have emphasized the importance of the estrogen-related receptor (ERR) family of nuclear receptors, master regulators of mitochondrial function, and their transcriptional coactivators PGC-1s in this context. In this review, we summarize key discoveries implicating the PGC-1/ERR axis in age-associated mitochondrial deregulation and tissue dysfunction. Also, we highlight the pharmacological potential of targeting the PGC-1/ERR axis to alleviate the onset of aging and its adverse effects.

/pdf/aging-senescence-and-mitochondria-the-pgc-1-err-axis-g5psjkv4or.pdf

Aging, senescence and mitochondria: the PGC-1/ERR axis.

Background A gradual decline in renal function occurs even in healthy aging individuals. In addition to aging per se, concurrent metabolic syndrome and hypertension, which are common in the aging population, can induce mitochondrial dysfunction and inflammation, which collectively contribute to age-related kidney dysfunction and disease. Here we studied the role of the nuclear hormone receptors, the estrogen-related receptors (ERRs) in regulation of age-related mitochondrial dysfunction and inflammation. ERRs were decreased in aging human and mouse kidneys and were preserved in aging mice with lifelong caloric restriction (CR). Methods A pan-ERR agonist was used to treat 21-month-old mice for 8-weeks. In addition, 21-month-old mice were treated with a STING inhibitor for 3 weeks. Results Remarkably, only an 8-week treatment with a pan-ERR agonist reversed the age-related increases in albuminuria, podocyte loss, mitochondrial dysfunction and inflammatory cytokines, including the cGAS-STING and STAT3 signaling pathways. A 3-week treatment of 21-month-old mice with a STING inhibitor reversed the increases in inflammatory cytokines and the senescence marker p21 but also unexpectedly reversed the age-related decreases in PGC-1α, ERRα, mitochondrial complexes and MCAD expression. Conclusions Our studies identified ERRs as important modulators of age-related mitochondrial dysfunction and inflammation. These findings highlight novel druggable pathways that can be further evaluated to prevent progression of age-related kidney disease. Significance Statement There is an increasing need for prevention and treatment strategies for age-related kidney disease. The hallmarks of aging kidneys are decreased mitochondrial function and increased inflammation. The expression of the nuclear hormone receptors estrogen-related receptors (ERRs) are decreased in aging human and mouse kidneys. This paper investigates the role of ERRs in the aging kidney. Treatment of aging mice with a pan-ERR agonist reversed the age-related increases in albuminuria and podocyte loss, mitochondrial dysfunction and inflammatory cytokines, including the cGAS-STING signaling pathways. Treatment of aging mice with a STING inhibitor decreased inflammation and increased mitochondrial gene expression. These findings identify ERRs as important modulators of age-related mitochondrial dysfunction and inflammation.

/pdf/estrogen-related-receptor-agonism-reverses-mitochondrial-2mb2dmjbe9.pdf

Estrogen-related receptor agonism reverses mitochondrial dysfunction and inflammation in the aging kidney

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Estrogen-related receptor agonism reverses mitochondrial dysfunction and inflammation in the aging kidney