Using Imaging Mass Cytometry to Define Cell Identities and Interactions in Human Tissues

In the evolving landscape of highly multiplexed imaging techniques that can be applied to study complex cellular microenvironments, this review characterizes the use of imaging mass cytometry (IMC) to study the human kidney. We provide technical details for antibody validation, cell segmentation, and data analysis specifically tailored to human kidney samples, and elaborate on phenotyping of kidney cell types and novel insights that IMC can provide regarding pathophysiological processes in the injured or diseased kidney. This review will provide the reader with the necessary background to understand both the power and the limitations of IMC and thus support better perception of how IMC analysis can improve our understanding of human disease pathogenesis and can be integrated with other technologies such as single cell sequencing and proteomics to provide spatial context to cellular data.

Unilateral Giant Hydronephrosis Secondary to Ureteropelvic Junction Obstruction in a Middle-Aged Woman

Background. Giant hydronephrosis is a rare urologic problem defined as a collection of more than one liter of urine in the collecting system. The radiologic appearance may mimic benign cystic disease of the kidney. We report a case of giant hydronephrosis in a 32-year-old female who presented with progressive abdominal swelling of two-year duration, caused by ureteropelvic junction obstruction with more than nine liters of urine in the collecting system. Conclusion. Giant hydronephrosis is a rare differential diagnosis for cystic intra-abdominal mass in adults with progressively increasing abdominal swelling. CT and MRI are important in confirming the diagnosis by localizing the origin of the swelling. Management depends on the underlying cause and appearance of the diseased kidney.

Myeloid heterogeneity in kidney disease as revealed through single cell RNA sequencing

Kidney disease represents a global health burden of increasing prevalence and is an independent risk factor for cardiovascular disease. Myeloid cells are a major cellular compartment of the immune system; they are found in the healthy kidney and in increased numbers in the damaged and/or diseased kidney, where they act as key players in the progression of injury, inflammation and fibrosis. They possess enormous plasticity and heterogeneity, adopting different phenotypic and functional characteristics in response to stimuli in the local milieu. Though this inherent complexity remains to be fully understood in the kidney, advances in single-cell genomics promises to change this. Specifically, single-cell RNA sequencing (scRNA-seq) has had a transformative effect on kidney research, enabling the profiling and analysis of the transcriptomes of single cells at unprecedented resolution and throughput, and subsequent generation of cell atlases. Moving forward, combining scRNA- and single-nuclear RNA-seq with greater resolution spatial transcriptomics will allow spatial mapping of kidney disease of varying aetiology to further reveal the patterning of immune cells and non-immune renal cells. This review summarises the roles of myeloid cells in kidney health and disease, the experimental workflow in currently available scRNA-seq technologies and published findings using scRNA-seq in the context of myeloid cells and the kidney.

Canonical Secretomes, Innate Immune Caspase-1-, 4/11-Gasdermin D Non-Canonical Secretomes and Exosomes May Contribute to Maintain Treg-Ness for Treg Immunosuppression, Tissue Repair and Modulate Anti-Tumor Immunity via ROS Pathways

We performed a transcriptomic analyses using the strategies we pioneered and made the following findings: 1) Normal lymphoid Tregs, diseased kidney Tregs, splenic Tregs from mice with injured muscle have 3, 17 and 3 specific (S-) pathways, respectively; 2) Tumor splenic Tregs share 12 pathways with tumor Tregs; tumor splenic Tregs and tumor Tregs have 11 and 8 S-pathways, respectively; 3) Normal and non-tumor disease Tregs upregulate some of novel 2641 canonical secretomic genes (SGs) with 24 pathways, and tumor Tregs upregulate canonical secretomes with 17 pathways; 4) Normal and non-tumor disease tissue Tregs upregulate some of novel 6560 exosome SGs with 56 exosome SG pathways (ESP), tumor Treg ESP are more focused than other Tregs; 5) Normal, non-tumor diseased Treg and tumor Tregs upregulate some of novel 961 innate immune caspase-1 SGs and 1223 innate immune caspase-4 SGs to fulfill their tissue/SG-specific and shared functions; 6) Most tissue Treg transcriptomes are controlled by Foxp3; and Tumor Tregs had increased Foxp3 non-collaboration genes with ROS and 17 other pathways; 7) Immune checkpoint receptor PD-1 does, but CTLA-4 does not, play significant roles in promoting Treg upregulated genes in normal and non-tumor disease tissue Tregs; and tumor splenic and tumor Tregs have certain CTLA-4-, and PD-1-, non-collaboration transcriptomic changes with innate immune dominant pathways; 8) Tumor Tregs downregulate more immunometabolic and innate immune memory (trained immunity) genes than Tregs from other groups; and 11) ROS significantly regulate Treg transcriptomes; and ROS-suppressed genes are downregulated more in tumor Tregs than Tregs from other groups. Our results have provided novel insights on the roles of Tregs in normal, injuries, regeneration, tumor conditions and some of canonical and innate immune non-canonical secretomes via ROS-regulatory mechanisms and new therapeutic targets for immunosuppression, tissue repair, cardiovascular diseases, chronic kidney disease, autoimmune diseases, transplantation, and cancers.

A.P. Langovoy. A case of pyonephrosis with the removal of a diseased kidney and uterine appendages. (Library of the Doctor, 1894, No. 3)

In March 1891, a patient, 33 years old, married, did not give birth, turned to the author with symptoms of cystitis. The undertaken treatment was of little use, on the contrary, soon there were even symptoms of a disease of the right kidney. Since the patient also had gynecological suffering, she was sent to the Moscow University Gynecological Clinic, where, according to the patient's examination, pyonephritis et salpyngo-oophoritis duplex was suggested. In May of the same year, it was performed by the patient prof. Snegirevym removal of the kidney and uterine appendages (the ovaries were found cystically degenerated, and the common tubes were calcified, thickened and adhered to the surrounding tissues).

Epigenetics of Diabetic Nephropathy: From Biology to Therapeutics

Diabetic nephropathy (DN) is a lethal microvascular complication associated with Type 1 and Type 2 diabetes mellitus, and is the leading single cause of end-stage renal disease. Although genetic influences are important, epigenetic mechanisms have been implicated in several aspects of the disease. The current therapeutic methods to treat DN are limited to slowing disease progression without repair and regeneration of the damaged nephrons. Replacing dying or diseased kidney cells with new nephrons is an attractive strategy. This review considers the genetic and epigenetic control of nephrogenesis, together with the epigenetic mechanisms that accompany kidney development and recent advances in induced reprogramming and kidney cell regeneration in the context of DN.

JAK2 is highly expressed by cyst-lining cells and regulates cystogenesis

ABSTRACTDysregulated JAK/STAT signalling is implicated in polycystic kidney disease, which is a common genetic disease leading to renal failure. However, the mechanisms underlying JAK/STAT-mediated cystogenesis arepoorlyunderstood.TheroleofJAK2wasinvestigated immunohistochemically in a murine model of cystic disease (Pkd1nl/nl). In the normal kidney, JAK2 is restricted to tubular epithelial and vascular cells with lesser staining in bowman’s capsule and is undetectable in the interstitium. By contrast, in the diseased kidney JAK2 appears stronger in cyst-lining cells when compared to normal tubules and appears mislocalised in the interstitium. Given that JAK2 is a major tyrosine kinase activating JAK/STAT, we considered whether its inhibition can attenuate cystic growth in vitro. To assess this we used curcumin, a natural phytochemical, which significantly reduced JAK2 levels and STAT3 activity. Consistently, reduced JAK2/STAT3 activity was correlated with reduced cystic growth of cystic cells in three-dimensional cyst assays. Taken together, our results suggest that JAK2 is a key signalling molecule that functions to inhibit cystic growth in cystic tubular epithelial cells, thus providing the foundation for its development as a novel therapeutic in polycystic kidney disease.