Renal Pathogenesis Research Articles

Recent findings on the role of microRNAs in genetic kidney diseases.

MicroRNAs (miRNAs) are non-coding, endogenous, single-stranded, small (21-25 nucleotides) RNAs. Various target genes at the post-transcriptional stage are modulated by miRNAs that are involved in the regulation of a variety of biological processes such as embryonic development, differentiation, proliferation, apoptosis, inflammation, and metabolic homeostasis. Abnormal miRNA expression is strongly associated with the pathogenesis of multiple common human diseases including cardiovascular diseases, cancer, hepatitis, and metabolic diseases. Various signaling pathways including transforming growth factor-β, apoptosis, and Wnt signaling pathways have also been characterized to play an essential role in kidney diseases. Most importantly, miRNA-targeted pharmaceutical manipulation has represented a promising new therapeutic approach against kidney diseases. Furthermore, miRNAs such as miR-30e-5p, miR-98-5p, miR-30d-5p, miR-30a-5p, miR-194-5p, and miR-192-5p may be potentially employed as biomarkers for various human kidney diseases. A significant correlation has also been found between some miRNAs and the clinical markers of renal function like baseline estimated glomerular filtration rate (eGFR). Classification of miRNAs in different genetic renal disorders may promote discoveries in developing innovative therapeutic interventions and treatment tools. Herein, the recent advances in miRNAs associated with renal pathogenesis, emphasizing genetic kidney diseases and development, have been summarized.

TREM-2 mediates dendritic cell-induced NO to suppress Th17 activation and ameliorate chronic kidney diseases.

Chronic kidney disease (CKD) is a global public health issue. CKD is caused by the infiltration of various myeloid cell types into renal tissue, resulting in renal fibrosis and tubular atrophy. Unilateral ureteral obstruction (UUO) surgery in mice is a model of CKD and characterized by high expression of the anti-inflammatory receptor, Triggering receptor expressed on myeloid cells 2 (TREM-2), on myeloid cells in affected kidneys. Here, we show that iNOS expression and nitric oxide (NO) induction were decreased in Trem-2-/- bone marrow-derived DCs (BMDCs) and in Trem-2 knockdown DC2.4 cells stimulated in vitro with LPS. The nitration of RORγt was decreased in T cells co-cultured with LPS-stimulated Trem-2-/- BMDCs, enhancing IL-17 production. UUO-treated Trem-2-/- mice displayed aggravated renal pathogenesis accompanied by greater neutrophil infiltration and enhanced Th17 cells differentiation, phenotypes that could be rescued by the administration of L-arginine (a biological precursor of NO). Our data identify a key mechanism underlying TREM-2-mediated NO to modulate the cellular crosstalk between dendritic cells, Th17, and neutrophils. Furthermore, we also reveal TREM-2 as a potential novel target for the development of anti-inflammatory drugs in CKD treatment. KEY MESSAGES: The expression of TREM-2 is increased in nephritis TREM-2+ DCs maintain NO production to negatively regulate Th17 differentiation The severe pathologies of nephritis can be rescued by L-arginine supplementation.

Association of Uremic Solutes With Cardiovascular Death in Diabetic Kidney Disease

Cardiovascular disease (CVD) is a major cause of mortality among people with diabetic kidney disease (DKD). The pathophysiology is inadequately explained by traditional CVD risk factors. The uremic solutes trimethylamine-N-oxide (TMAO) and asymmetric and symmetric dimethylarginine (ADMA, SDMA) have been linked to CVD in kidney failure with replacement therapy (KFRT), but data are limited in populations with diabetes and less severe kidney disease. Observational cohort. Random subcohort of 555 REGARDS (Reasons for Geographic and Racial Differences in Stroke) study participants with diabetes and estimated glomerular filtration rate (eGFR)<60 mL/min/1.73 m2 at study entry. ADMA, SDMA, and TMAO assayed by liquid chromatography-mass spectrometry in plasma and urine. Cardiovascular mortality (primary outcome); all-cause mortality and incident KFRT (secondary outcomes). Plasma concentrations and ratios of urine to plasma concentrations of ADMA, SDMA, and TMAO were tested for association with outcomes. Adjusted Cox regression models were fitted and hazard ratios of outcomes calculated per standard deviation and per doubling, and as interquartile comparisons. The mean baseline eGFR was 44 mL/min/1.73 m2. Cardiovascular death, overall mortality, and KFRT occurred in 120, 285, and 89 participants, respectively, during a mean 6.2 years of follow-up. Higher plasma ADMA and SDMA (HRs of 1.20 and 1.28 per 1-SD greater concentration), and lower ratios of urine to plasma concentrations of ADMA, SDMA, and TMAO (HRs per halving of 1.53, 1.69, and 1.38) were associated with cardiovascular mortality. Higher plasma concentrations of ADMA, SDMA, and TMAO (HRs of 1.31, 1.42, and 1.13 per 1-SD greater concentration) and lower urine to plasma ratios of ADMA, SDMA, and TMAO (HRs per halving of 1.34, 1.37, and 1.26) were associated with all-cause mortality. Higher plasma ADMA and SDMA were associated with incident KFRT by categorical comparisons (HRs of 2.75 and 2.96, comparing quartile 4 to quartile 1), but not in continuous analyses. Single cohort, restricted to patients with diabetes and eGFR< 60 mL/min/1.73 m2, potential residual confounding by GFR, no dietary information. Higher plasma concentrations and lower ratios of urine to plasma concentrations of uremic solutes were independently associated with cardiovascular and all-cause mortality in DKD. Associations of ratios of urine to plasma concentrations with mortality suggest a connection between renal uremic solute clearance and CVD pathogenesis.

Clr-f expression regulates kidney immune and metabolic homeostasis

The C-type lectin-related protein, Clr-f, encoded by Clec2h in the mouse NK gene complex (NKC), is a member of a family of immune regulatory lectins that guide immune responses at distinct tissues of the body. Clr-f is highly expressed in the kidney; however, its activity in this organ is unknown. To assess the requirement for Clr-f in kidney health and function, we generated a Clr-f-deficient mouse (Clr-f−/−) by targeted deletions in the Clec2h gene. Mice lacking Clr-f exhibited glomerular and tubular lesions, immunoglobulin and C3 complement protein renal deposits, and significant abdominal and ectopic lipid accumulation. Whole kidney transcriptional profile analysis of Clr-f−/− mice at 7, 13, and 24 weeks of age revealed a dynamic dysregulation in lipid metabolic processes, stress responses, and inflammatory mediators. Examination of the immune contribution to the pathologies of Clr-f−/− mouse kidneys identified elevated IL-12 and IFNγ in cells of the tubulointerstitium, and an infiltrating population of neutrophils and T and B lymphocytes. The presence of these insults in a Rag1−/−Clr-f−/− background reveals that Clr-f−/− mice are susceptible to a T and B lymphocyte-independent renal pathogenesis. Our data reveal a role for Clr-f in the maintenance of kidney immune and metabolic homeostasis.

Vitamin C Deficiency Causes Cell Type-Specific Epigenetic Reprogramming and Acute Tubular Necrosis in a Mouse Model.

Vitamin C deficiency is found in patients with variable kidney diseases. However, the role of vitamin C as an epigenetic regulator in renal homeostasis and pathogenesis remains largely unknown. We showed that vitamin C deficiency leads to acute tubular necrosis (ATN) using a vitamin C-deficient mouse model (Gulo knock-out). DNA/RNA epigenetic modifications and injured S3 proximal tubule cells were identified in the vitamin C-deficient kidneys using whole-genome bisulfite sequencing, methylated RNA immunoprecipitation sequencing, and single-cell RNA sequencing. Integrated evidence suggested that epigenetic modifications affected the proximal tubule cells and fenestrated endothelial cells, leading to tubule injury and hypoxia through transcriptional regulation. Strikingly, loss of DNA hydroxymethylation and DNA hypermethylation in vitamin C-deficient kidneys preceded the histologic sign of tubule necrosis, indicating the causality of vitamin C-induced epigenetic modification in ATN. Consistently, prophylactic supplementation of an oxidation-resistant vitamin C derivative, ascorbyl phosphate magnesium, promoted DNA demethylation and prevented the progression of cisplatin-induced ATN. Vitamin C played a critical role in renal homeostasis and pathogenesis in a mouse model, suggesting vitamin supplementation may be an approach to lower the risk of kidney injury.

Differentiation of CD117+ Amniotic Fluid Stem Cells towards Nephron Progenitors.

Objective:The study aimed at isolation of CD117+ stem cells from amniotic fluid samples followed by their invitro differentiation towards nephron progenitors that can be potentially used for regenerative medicine studies and to further understand pathways involved in renal pathogenesisMethods:This experimental study was conducted at Dow Research Institute of Biotechnology and Biomedical Sciences (DRIBBS), Dow University of Health Sciences, OJHA Campus Karachi from November 2019 to December 2020. After patient consent, a Pfannenstiel incision was performed by the gynecologist through abdominal and uterine muscles without cutting into Amniotic Membrane. Using a needle of 5CC syringe connected to sterile Redivac bottle, a blunt end insertion was passed through the membrane and the amniotic fluid was aseptically sucked into Redivac bottle, the ice bag was used for transporting amniotic fluid from hospital to the lab and samples were processed within 60 minutes after collection. Amniotic fluid was centrifuged at 4º C for 20 minutes at 1400xg. After centrifugation the cell pellet was treated for analysis of CD117+ cells using flowcytometry, once small percentage of CD117+ cells were identified the cells were prepared for differentiation and that was carried out using specific growth factors including BMP4, BMP7, FGF2, and retinoic acid, providing the niche to the stem cells for differentiation towards nephron progenitors which was confirmed by protein expression of Wilms Tumor-1 (WT1) using immunofluorescence analysis. The sample size for this invitro work was n=3.Results:We successfully isolated small percentage of CD117+ cells in amniotic fluid followed by in vitro expansion and differentiation towards nephron progenitor cells (NPCs) using well defined media and growth factors, initially differentiated cells were spindle shaped and showed fibroblastic appearance later at stage of nephron progenitors it attained the shape of rounded big clusters, differentiated cells stained positive for WT1 and negative for cluster of differentiation (CD117). Therefore, confirming the successful isolation and differentiation of amniotic fluid stem cells towards nephron progenitors.Conclusion:To the best of our knowledge this is the first study from the country on the use of Amniotic fluid stem cells and their differentiation towards nephron progenitors that can be used as substitution source of cell therapy for exploration of renal diseases at cellular and molecular level and potential regenerative medicine applications.

Association of C5a/C5aR pathway to activate ERK1/2 and p38 MAPK in acute kidney injury – a mouse model

Abstract Acute inflammation is accompanied by complement system activation and inflammatory cell accumulation. Acute kidney injury (AKI) is one of the common clinical symptoms, it is not clear whether complement system-mediated signaling pathway is involved. This study demonstrated that the expressions of complement C5a and C5a receptor (C5aR) protein in a mouse model with glycerol induced AKI were significantly increased, and the expression of inflammatory cytokines, such as IL-1β, IL-6 and TNF-α, were significantly higher than those in the blank control group. While C5aR antagonist (C5aRa) was added, western analyses for C5a and C5aR were reduced, meanwhile, qPCR and ELISA data showed that inflammatory cytokines also decreased significantly. In addition, preliminarily explored, the Mitogen-activated protein kinases (MAPKs) can be activated by the C5a/C5aR pathway in an AKI mouse model which showed that the C5a/C5aR pathway in a mouse model group activated ERK1/2 and p38, and the protein expression decreased when C5aRa was added. In conclusion, these results indicate that the C5a/C5aR pathway promotes renal pathogenesis by activating ERK1/2 and p38 expression and then affects the disease process, which has certain guiding significance for the subsequent clinical trial.

Immune-Mediated Renal Diseases: A Team-Based Learning Module for Preclinical Medical Students.

IntroductionThe underlying immune mechanisms of renal diseases are complex, and medical students benefit from learning these complexities in the setting of team-based learning (TBL), where they can apply foundational immunologic concepts to clinical problems.MethodsThis immune-mediated renal disease TBL module focusing on glomerular disease was delivered over a period of 2 consecutive years in an integrated cardiovascular, pulmonary, and renal block within the second semester of the first year of medical school. Each class consisted of 53 students, for a total of 106 students. The TBL module consisted of a seven-question individual and team readiness assurance test (iRAT and tRAT) and two clinically relevant team application activities. Following the TBL module, students completed an 18-item survey that collected information on student perspectives of engagement.ResultsFor the 2-year period, the iRAT average scores were 73% and 74%, and the tRAT average scores were 100% and 99%, respectively. The survey assessing student perceptions of engagement yielded positive feedback.DiscussionIn summary, this TBL module effectively integrates the foundational and clinical sciences to teach higher-order concepts in immunology and renal disease pathogenesis to medical students.

FcER1: A Novel Molecule Implicated in the Progression of Human Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is a key microvascular complication of diabetes, with few therapies for targeting renal disease pathogenesis and progression. We performed transcriptional and protein studies on 103 unique blood and kidney tissue samples from patients with and without diabetes to understand the pathophysiology of DKD injury and its progression. The study was based on the use of 3 unique patient cohorts: peripheral blood mononuclear cell (PBMC) transcriptional studies were conducted on 30 patients with DKD with advancing kidney injury; Gene Expression Omnibus (GEO) data was downloaded, containing transcriptional measures from 51 microdissected glomerulous from patients with DKD. Additionally, 12 independent kidney tissue sections from patients with or without DKD were used for validation of target genes in diabetic kidney injury by kidney tissue immunohistochemistry and immunofluorescence. PBMC DKD transcriptional analysis, identified 853 genes (p < 0.05) with increasing expression with progression of albuminuria and kidney injury in patients with diabetes. GEO data was downloaded, normalized, and analyzed for significantly changed genes. Of the 325 significantly up regulated genes in DKD glomerulous (p < 0.05), 28 overlapped in PBMC and diabetic kidney, with perturbed FcER1 signaling as a significantly enriched canonical pathway. FcER1 was validated to be significantly increased in advanced DKD, where it was also seen to be specifically co-expressed in the kidney biopsy with tissue mast cells. In conclusion, we demonstrate how leveraging public and private human transcriptional datasets can discover and validate innate immunity and inflammation as key mechanistic pathways in DKD progression, and uncover FcER1 as a putative new DKD target for rational drug design.

Emerging Insights Into Chronic Renal Disease Pathogenesis in Hypertension From Human and Animal Genomic Studies.

The pathogenic links between elevated blood pressure and chronic kidney disease remain obscure. This article examines progress in population genetics and in animal models of hypertension and chronic kidney disease. It also provides a critique of the application of genome-wide association studies to understanding the heritability of renal function. Emerging themes identified indicate that heritable risk of chronic kidney disease in hypertension can arise from genetic variation in (1) glomerular and tubular protein handling mechanisms; (2) autoregulatory capacity of the renal vasculature; and (3) innate and adaptive immune mechanisms. Increased prevalence of hypertension-associated chronic kidney disease that occurs with aging may reflect amplification of heritable risks by normal aging processes affecting immunity and autoregulation.

Carbon Monoxide in Renal Physiology, Pathogenesis and Treatment of Renal Disease.

Carbon monoxide (CO) is one of the endogenous gaseous messengers or gasotransmitters, and is a paramount mediator in physiological and disease conditions. In this review, we focus on the functions of CO in normal and pathological renal physiology. We discuss endogenous renal CO production and signaling in the normal kidney, the characteristic of CO-releasing molecules (CORMs) modalities, and outline its regulatory functions in renal physiology. This article summarizes the mechanisms as well as the effect of CO in the evolving field of renal diseases. We predict numerous innovative CO applications forevolvingcutting-edge scholarly work in the future.

Emerging Role of Neuropilin-1 and Angiotensin-Converting Enzyme-2 in Renal Carcinoma-Associated COVID-19 Pathogenesis.

Neuropilin-1 (NRP1) is a recently identified glycoprotein that is an important host factor for SARS-CoV-2 infection. On the other hand, angiotensin-converting enzyme-2 (ACE2) acts as a receptor for SARS-CoV-2. Additionally, both NRP1 and ACE2 express in the kidney and are associated with various renal diseases, including renal carcinoma. Therefore, the expression profiles of NRP1 and ACE2 in kidney renal clear cell carcinoma (KIRC) and kidney renal papillary cell carcinoma (KIRP) patients from the various cancer databases were investigated along with their impact on patients’ survivability. In addition, coexpression analysis of genes involved in COVID-19, KIRC, and KIRP concerning NRP1 and ACE2 was performed. The results demonstrated that both t NRP1 and ACE2 expressions are upregulated in KIRC and KIRP compared to healthy conditions and are significantly correlated with the survivability rate of KIRC patients. A total of 128 COVID-19-associated genes are coexpressed, which are positively associated with NRP1 and ACE2 both in KIRC and KIRP. Therefore, it might be suggested that, along with the ACE2, high expression of the newly identified host factor NRP1 in renal carcinomas may play a vital role in the increased risk of SARS-CoV-2 infection and survivability of COVID-19 patients suffering from kidney cancers. The findings of this investigation will be helpful for further molecular studies and prevention and/or treatment strategies for COVID-19 patients associated with renal carcinomas.

Gender and Sexual Orientation Disparities in Smoking, Cadmium Exposure, and Estimated GFR: National Health and Nutrition Examination Survey 2005-2014

BACKGROUND AND AIM: Chronic kidney disease (CKD) is a progressive disease characterized by structural, molecular, and functional nephron changes that eventually result in permanent loss of function. CKD can lead to heart disease, stroke, and end stage kidney disease. Studies have linked cadmium exposure to decreased glomerular filtration rate (GFR) and renal pathogenesis. The main non-occupational pathway for cadmium exposure is from tobacco smoke. Lesbian, gay, and bisexual (LGB) individuals have one of the highest subpopulation smoking rates, yet studies have not examined if they have higher cadmium exposure or renal disease burden. The aim of this study was to evaluate gender and sexual orientation disparities in cadmium exposure and estimated glomerular filtration rate (eGFR) in the National Health and Nutrition Examination Survey (NHANES) from 2005-2014 in 16,576 individuals. METHODS: The analysis used a combination of geometric means and survey linear regression to evaluate cadmium burden and eGFR. RESULTS:The percentage of smokers among LGB participants was higher (44.2%) than in straight participants (28.7%). Comparing geometric mean blood cadmium of males showed that straight men have the lowest cadmium levels (0.297 ng/L) and bisexual men have the highest cadmium levels (0.347 ng/L). Among females, straight females have the lowest cadmium levels (0.354 ng/L) and gay females have the highest cadmium levels (0.446 ng/L). There were statistically significant differences between odds ratios of low eGFR by gender and sexual orientation. Compared to straight males, the odds ratio for low eGFR among gay males was 0.824 (95% CI 0.820, 0.827; p0.0003) bisexual males was 0.634 (95% CI 0.549, 0.555; p0.0001), straight females was 0.844 (95% CI 0.843, 0.845; p0.0001), gay females was 0.783 (95% CI 0.778, 0.788; p0.0001), and bisexual females was 1.092 (95% CI 1.089, 1.096; p0.0001). CONCLUSIONS:This analysis highlights the need for additional research specifically addressing disparities related to gender identity and sexual orientation. KEYWORDS: NHANES, cadmium, kidney disease, sexual orientation, gender, disparities

Targeting the Wnt/β-Catenin Signaling Pathway as a Potential Therapeutic Strategy in Renal Tubulointerstitial Fibrosis.

The Wnt/β-catenin signaling pathway plays important roles in embryonic development and tissue homeostasis. Wnt signaling is induced, and β-catenin is activated, associated with the development and progression of renal fibrosis. Wnt/β-catenin controls the expression of various downstream mediators such as snail1, twist, matrix metalloproteinase-7, plasminogen activator inhibitor-1, transient receptor potential canonical 6, and renin-angiotensin system components in epithelial cells, fibroblast, and macrophages. In addition, Wnt/β-catenin is usually intertwined with other signaling pathways to promote renal interstitial fibrosis. Actually, given the crucial of Wnt/β-catenin signaling in renal fibrogenesis, blocking this signaling may benefit renal interstitial fibrosis. There are several antagonists of Wnt signaling that negatively control Wnt activation, and these include soluble Fzd-related proteins, the family of Dickkopf 1 proteins, Klotho and Wnt inhibitory factor-1. Furthermore, numerous emerging small-molecule β-catenin inhibitors cannot be ignored to prevent and treat renal fibrosis. Moreover, we reviewed the knowledge focusing on anti-fibrotic effects of natural products commonly used in kidney disease by inhibiting the Wnt/β-catenin signaling pathway. Therefore, in this review, we summarize recent advances in the regulation, downstream targets, role, and mechanisms of Wnt/β-catenin signaling in renal fibrosis pathogenesis. We also discuss the therapeutic potential of targeting this pathway to treat renal fibrosis; this may shed new insights into effective treatment strategies to prevent and treat renal fibrosis.

Hantavirus infection-induced B cell activation elevates free light chains levels in circulation.

In humans, orthohantaviruses can cause hemorrhagic fever with renal syndrome (HFRS) or hantavirus pulmonary syndrome (HPS). An earlier study reported that acute Andes virus HPS caused a massive and transient elevation in the number of circulating plasmablasts with specificity towards both viral and host antigens suggestive of polyclonal B cell activation. Immunoglobulins (Igs), produced by different B cell populations, comprise heavy and light chains; however, a certain amount of free light chains (FLCs) is constantly present in serum. Upregulation of FLCs, especially clonal species, associates with renal pathogenesis by fibril or deposit formations affecting the glomeruli, induction of epithelial cell disorders, or cast formation in the tubular network. We report that acute orthohantavirus infection increases the level of Ig FLCs in serum of both HFRS and HPS patients, and that the increase correlates with the severity of acute kidney injury in HFRS. The fact that the kappa to lambda FLC ratio in the sera of HFRS and HPS patients remained within the normal range suggests polyclonal B cell activation rather than proliferation of a single B cell clone. HFRS patients demonstrated increased urinary excretion of FLCs, and we found plasma cell infiltration in archival patient kidney biopsies that we speculate to contribute to the observed FLC excreta. Analysis of hospitalized HFRS patients' peripheral blood mononuclear cells showed elevated plasmablast levels, a fraction of which stained positive for Puumala virus antigen. Furthermore, B cells isolated from healthy donors were susceptible to Puumala virus in vitro, and the virus infection induced increased production of Igs and FLCs. The findings propose that hantaviruses directly activate B cells, and that the ensuing intense production of polyclonal Igs and FLCs may contribute to acute hantavirus infection-associated pathological findings.

Aim2 Couples With Ube2i for Sumoylation-Mediated Repression of Interferon Signatures in Systemic LupusErythematosus.

Systemic lupus erythematosus (SLE) involves kidney damage, and the inflammasome-caspase-1 axis has been demonstrated to promote renal pathogenesis. The present study was designed to explore the function of the Absent in Melanoma 2 (Aim2) protein in SLE. Female wild-type Aim2-/- , Aim2-/- Ifnar1-/- , Aim2-/- Rag1-/- , and Asc-/- mice ages 8-10 weeks received 1 intraperitoneal injection of 500 μl pristane or saline, and survival of mice was monitored twice a week for 6 months. The absence of Aim2, but not Asc, led to enhanced SLE in mice that received pristane treatment. Increased immune cell infiltration and type I interferon (IFN) signatures in the kidneys of Aim2-/- mice coincided with severity of lupus, which was alleviated by blockade of Ifnar1-mediated signal. Adaptive immune cells were also involved in the glomerular lesions of Aim2-/- mice after pristane challenge. Importantly, even in the absence of pristane, plasmacytoid dendritic cells in the kidneys of Aim2-/- mice were significantly increased compared to control animals. Accordingly, transcriptome analysis revealed that Aim2 deficiency led to enhanced expression of type I IFN-induced genes in the kidneys even at an early developmental stage. Mechanistically, Aim2 bound ubiquitin-conjugating enzyme 2i (Ube2i), which mediates sumoylation-based suppression of type I IFN expression deficiency of Aim2 decreased cellular sumoylation, resulting in an augmented type I IFN signature and kidney pathogenesis. The present study demonstrates a critical role for Aim2 in an optimal Ube2i-mediated sumoylation-based suppression of type I IFN generation and development of SLE. As such, the Aim2-Ube2i axis can thus be a novel target for intervention in SLE.

Renal manifestations, incidence, pathogenesis and implications on prognosis and mortality in COVID-19 patients: A review of current evidence and the potential for future directions.

Coronavirus disease 2019 (COVID-19) is a highly infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has now spread into a worldwide pandemic. The pulmonary manifestations of this disease have been well described in literature, however COVID-19 can also cause severe and lasting harm in other organs including the kidneys, heart, and pancreas. Emerging evidence suggests that COVID-19 has multiple renal manifestations which impact the prognosis and mortality of this disease. Here we present a literature review of the current evidence of renal involvement in COVID-19 patients and the potential for future directions in management.

PI3K/AKT/mTOR signalling pathway involvement in renal cell carcinoma pathogenesis (Review).

Renal cell carcinoma (RCC) accounts for over 90% of all renal malignancies, and mainly affects the male population. Obesity and smoking are involved in the pathogenesis of several systemic cancers including RCC. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway regulates cell growth, differentiation, migration, survival, angiogenesis, and metabolism. Growth factors, hormones, cytokine and many extracellular cues activate PI3K/AKT/mTOR. Dysregulation of this molecular pathway is frequently reported in human cancers including RCC and is associated with aggressive development and poor survival rate. mTOR is the master regulator of cell metabolism and growth, and is activated in many pathological processes such as tumour formation, insulin resistance and angiogenesis. mTOR inhibitors are used at present as drug therapy for RCC to inhibit cell proliferation, growth, survival, and the cell cycle. Temsirolimus and everolimus are two mTOR inhibitors that are currently used for the treatment of RCC. Drugs targeting the PI3K/AKT/mTOR signalling pathway may be one of the best therapeutic options for RCC.

Testosterone Metabolite 6β‐Hydroxytestosterone Contributes to Angiotensin II‐Induced Abdominal Aortic Aneurysms in Apoe –/– Male Mice

BackgroundSex is a prominent risk factor for abdominal aortic aneurysms (AAAs), and angiotensin II (Ang II) induces AAA formation to a greater degree in male than in female mice. We previously reported that cytochrome P450 1B1 contributes to the development of hypertension, as well as AAAs, in male mice. We also found that a cytochrome P450 1B1‐generated metabolite of testosterone, 6β‐hydroxytestosterone (6β‐OHT), contributes to Ang II‐induced hypertension and associated cardiovascular and renal pathogenesis in male mice. The current study was conducted to determine the contribution of 6β‐OHT to Ang II‐induced AAA development in Apoe–/– male mice.Methods and ResultsIntact or castrated Apoe–/–/Cyp1b1+/+ and Apoe–/–/Cyp1b1–/– male mice were infused with Ang II or its vehicle for 28 days, and administered 6β‐OHT every third day for the duration of the experiment. Abdominal aortas were then evaluated for development of AAAs. We observed a significant increase in the incidence and severity of AAAs in intact Ang II‐infused Apoe–/–/Cyp1b1+/+ mice, compared with vehicle‐treated mice, which were minimized in castrated Apoe–/–/Cyp1b1+/+ and intact Apoe–/–/Cyp1b1–/– mice infused with Ang II. Treatment with 6β‐OHT significantly restored the incidence and severity of AAAs in Ang II‐infused castrated Apoe–/–/Cyp1b1+/+ and intact Apoe–/–/Cyp1b1–/– mice. However, administration of testosterone failed to increase AAA incidence and severity in Ang II‐infused intact Apoe–/–/Cyp1b1–/– mice.ConclusionsOur results indicate that the testosterone‐cytochrome P450 1B1‐generated metabolite 6β‐OHT contributes to Ang II‐induced AAA development in Apoe–/– male mice.

Castrated autoimmune glomerulonephritis mouse model shows attenuated glomerular sclerosis with altered parietal epithelial cell phenotype.

Sex hormones help in maintaining proper immunity as well as renal homeostasis in mammals, and these multi-functional properties characterize the onset of sex-dependent diseases. To clarify the contribution of sex hormones to autoimmune disease-related renal pathogenesis, BXSB/MpJ-Yaa was investigated as a murine autoimmune glomerulonephritis model. BXSB/MpJ-Yaa and its wild-type, BXSB/MpJ-Yaa+ were castrated or sham-operated at three weeks and examined until six months of age. Both castrated strains showed significantly lower serum testosterone levels and body weights than sham-operated mice. Castration did not change the disease phenotypes in BXSB/MpJ-Yaa+. At three months, both sham-operated and castrated BXSB/MpJ-Yaa manifested splenomegaly, autoantibody production, and glomerulonephritis, and castrated BXSB/MpJ-Yaa tended to show heavier spleen weights than the sham-operated group. At six months, both the treated BXSB/MpJ-Yaa showed equivalent autoimmune disease conditions; however, castrated mice clearly showed milder glomerular sclerotic lesions than the sham-operated groups. Urinary albumin excretion in castrated BXSB/MpJ-Yaa was significantly milder than in sham-operated mice at four months, but those of both the treated BXSB/MpJ-Yaa were comparable at six months. The examined renal histopathological indices in parietal epithelial cells were remarkably altered by castration. Briefly, castration decreased the height of parietal epithelial cells and total parietal epithelial cell number in BXSB/MpJ-Yaa at six months. For immunostaining, parietal epithelial cells facing the injured glomeruli of BXSB/MpJ-Yaa expressed CD44, an activated parietal epithelial cell marker, and CD44-positive parietal epithelial cells showed nuclear localization of the androgen receptor and proliferation marker Ki67. CD44- or Ki67-positive parietal epithelial cells were significantly fewer in castrated group than in sham-operated BXSB/MpJ-Yaa at six months. Further, quantitative indices for CD44-positive parietal epithelial cell number and frequency in renal corpuscles positively correlated with glomerular sclerotic severity in BXSB/MpJ-Yaa. In conclusion, androgen seemed to have an effect on both systemic immunity and renal morpho-function; however, the effect on the latter could be more clearly observed in BXSB/MpJ-Yaa, as parietal epithelial cell activation resulted in glomerular sclerosis.