Factors associated with risk analysis for asymptomatic left ventricular diastolic dysfunction in nondialysis patients with chronic kidney disease.

Heart failure (HF) constitutes a major determinant of outcome in chronic kidney disease (CKD) patients. The main pattern of HF in CKD patients is preserved ejection fraction (HFpEF), and left ventricular diastolic dysfunction (LVDD) is a frequent pathophysiological mechanism and specific preclinical manifestation of HFpEF. Therefore, exploring and intervention of the factors associated with risk for LVDD is of great importance in reducing the morbidity and mortality of cardiovascular disease (CVD) complications in CKD patients. We designed this retrospective cross-sectional study to collect clinical and echocardiographic data from 339 nondialysis CKD patients without obvious symptoms of HF to analyze the proportion of asymptomatic left ventricular diastolic dysfunction (ALVDD) and its related factors associated with risk by multivariate logistic regression analysis. Among the 339 nondialysis CKD patients, 92.04% had ALVDD. With the progression of CKD stage, the proportion of ALVDD gradually increased. The multivariate logistic regression analysis revealed that increased age (OR 1.237; 95% confidence interval (CI) 1.108-1.381, per year), diabetic nephropathy (DN) and hypertensive nephropathy (HTN) (OR 25.000; 95% CI 1.355-48.645, DN and HTN vs chronic interstitial nephritis), progression of CKD stage (OR 2.785; 95% CI 1.228-6.315, per stage), increased mean arterial pressure (OR 1.154; 95% CI 1.051-1.268, per mmHg), increased urinary protein (OR 2.825; 95% CI 1.484-5.405, per g/24 h), and low blood calcium (OR 0.072; 95% CI 0.006-0.859, per mmol/L) were factors associated with risk for ALVDD in nondialysis CKD patients after adjusting for other confounding factors. Therefore, dynamic monitoring of these factors associated with risk, timely diagnosis and treatment of ALVDD can delay the progression to symptomatic HF, which is of great importance for reducing CVD mortality, and improving the prognosis and quality of life in CKD patients.

Zyxin is important for the stability and function of podocytes, especially during mechanical stretch.

Podocyte detachment due to mechanical stress is a common issue in hypertension-induced kidney disease. This study highlights the role of zyxin for podocyte stability and function. We have found that zyxin is significantly up-regulated in podocytes after mechanical stretch and relocalizes from focal adhesions to actin filaments. In zyxin knockout podocytes, we found that the loss of zyxin reduced the expression of vinculin and VASP as well as the expression of matrix proteins, such as fibronectin. This suggests that zyxin is a central player in the translation of mechanical forces in podocytes. In vivo, zyxin is highly up-regulated in patients suffering from diabetic nephropathy and in hypertensive DOCA-salt treated mice. Furthermore, zyxin loss in mice resulted in proteinuria and effacement of podocyte foot processes that was measured by super resolution microscopy. This highlights the essential role of zyxin for podocyte maintenance in vitro and in vivo, especially under mechanical stretch.

Mechanisms of inflammation modulation by different immune cells in hypertensive nephropathy.

Hypertensive nephropathy (HTN) is the second leading cause of end-stage renal disease (ESRD) and a chronic inflammatory disease. Persistent hypertension leads to lesions of intrarenal arterioles and arterioles, luminal stenosis, secondary ischemic renal parenchymal damage, and glomerulosclerosis, tubular atrophy, and interstitial fibrosis. Studying the pathogenesis of hypertensive nephropathy is a prerequisite for diagnosis and treatment. The main cause of HTN is poor long-term blood pressure control, but kidney damage is often accompanied by the occurrence of immune inflammation. Some studies have found that the activation of innate immunity, inflammation and acquired immunity is closely related to the pathogenesis of HTN, which can cause damage and dysfunction of target organs. There are more articles on the mechanism of diabetic nephropathy, while there are fewer studies related to immunity in hypertensive nephropathy. This article reviews the mechanisms by which several different immune cells and inflammatory cytokines regulate blood pressure and renal damage in HTN. It mainly focuses on immune cells, cytokines, and chemokines and inhibitors. However, further comprehensive and large-scale studies are needed to determine the role of these markers and provide effective protocols for clinical intervention and treatment.

The effect of primary renal disease upon outcomes after renal transplant.

BACKGROUND: This study investigated whether nature of primary renal disease affects clinical outcomes after renal transplantation at a single center in the United Kingdom. METHODS: This was a retrospective cohort study of 961 renal transplant recipients followed up at a large renal center from 2000 to 2020. Separation of diseases responsible for end-stage kidney disease included glomerulonephritis, diabetic kidney disease, hypertensive nephropathy, autosomal dominant polycystic kidney disease, unknown cause, other causes and chronic pyelonephritis. Outcome data included graft loss, cardiovascular events, malignancy, post-transplant diabetes mellitus and death, analyzed according to primary disease type. RESULTS: The mean age at transplantation was 47.3 years. During a mean follow-up of 7.6 years, 18% of the overall cohort died corresponding to an annualised mortality rate of 2.3%. Death with a functioning graft occurred at a rate of 2.1% per annum, with the highest incidence observed in in patients with diabetic kidney disease (4.1%/year). Post-transplant cardiovascular events occurred in 21% of recipients (2.8% per year), again highest in recipients with diabetic kidney disease (5.1%/year) and hypertensive nephropathy (4.5%/year). Post-transplant diabetes mellitus manifested in 19% of the cohort at an annualized rate of2.1% while cancer incidence stood at 9% with an annualized rate of 1.1% . Graft loss occurred in 6.8% of recipients at the rate of1.2% per year with chronic allograft injury, acute rejection and recurrent glomerulonephritis being the predominant causative factors. Median + IQR dialysis-free survival of the whole cohort was 16.2 (9.9 - > 20) years, being shortest for diabetic kidney disease (11.0 years) and greatest for autosomal dominant polycystic kidney disease (18.2 years) .The collective mean decline in eGFR over time was -1.14ml/min/year. Recipients with Pre-transplant diabetic kidney disease exhibited the fastest rate of decline(-2.1ml/min/year) a statistically significant difference in comparison to the other native kidney diseases with Autosomal dominant polycystic kidney disease exhibiting the lowest rate of decline(-0.05ml/min/year) CONCLUSION: Primary renal disease can influence the outcome after renal transplantation, with patients with prior diabetic kidney disease having the poorest outcome in terms of dialysis-free survival and loss of transplant function. Autosomal polycystic kidney disease, other cause and unknown cause had the best outcomes compared to other primary renal disease groups.

GPR97 deficiency suppresses Wnt/ß-catenin signaling in hypertensive nephropathy.

Accumulating evidence shows that renal fibrosis plays a key role in the development of hypertensive nephropathy (HTN). Therefore, a better understanding of the underlying mechanism of renal fibrosis regulation in HTN would be critical for designing rational strategies for therapeutic interventions. In this study, we revealed that GPR97, a novel identified adhesion G coupled receptor, plays an important role in the regulation of Wnt/ß-catenin signaling, which is the crucial driver of renal fibrosis in HTN. First, we identified that the expression of GPR97 correlated with the ß-catenin expression in renal biopsy from patients with HTN. Moreover, we found that GPR97 deficiency inhibited Wnt/ß-catenin signaling in mice with HTN, as evidenced by the reduction of ß-catenin expression and downstream target proteins, including MMP7 and Fibronectin. Mechanistically, we found that GPR97 could directly bind with Wnt1 in cultured tubular cells and TGF-ß1 treatment enhanced the binding ability of GPR97 and Wnt1. In addition, the gene silencing of GPR97 could decrease the Wnt1-induced fibrotic phenotype of tubular cells and inflammatory responses, suggesting that the binding of GPR97 and Wnt1 promoted Wnt/ß-catenin signaling. Collectively, our studies reveal that GPR97 is a regulator of Wnt/ß-catenin signaling in HTN, and targeting GPR97 may be a novel therapeutic strategy for HTN treatment.

Risk factor control and cardiovascular events in patients with type 2 diabetes mellitus.

BACKGROUND: Since patients with type 2 diabetes mellitus (T2DM) have an increased risk of cardiovascular events, interventions addressing risk factors reduce the incidence of cardiovascular disease (CVD) events. This study aimed to evaluate the difference in the incidence of CVD events according to risk factor control in patients with diabetes with and without cardio-renal disease. METHODS: We analyzed 113,909 patients with diabetes and 290,339 without diabetes using data released by the National Health Insurance Service (NHIS). RESULTS: Among patients with diabetes with four or five poorly controlled risk factors, hazard ratio for CVD events was 1.19 (95% confidence interval [CI], 1.06-1.34) in patients with cardio-renal disease and 2.31 (95% CI, 1.95-2.74) in patients without cardio-renal disease compared to patients with diabetes without risk factors. In subjects with diabetes and cardio-renal disease, patients with four or five poorly controlled risk factors had a higher risk of CVD mortality compared to subjects without risk factors (hazard ratio, 1.64; 95% CI, 1.18-2.30). CONCLUSION: Controlling cardiovascular risk factors reduced the incidence of CVD events in patients with diabetes, especially those without cardio-renal disease. The degree of risk control was strongly associated with CVD mortality in patients with diabetes with baseline cardio-renal disease.

Current perspectives and trends of the research on hypertensive nephropathy: a bibliometric analysis from 2000 to 2023.

Hypertensive nephropathy continues to be a major cause of end-stage renal disease and poses a significant global health burden. Despite the staggering development of research in hypertensive nephropathy, scientists and clinicians can only seek out useful information through articles and reviews, it remains a hurdle for them to quickly track the trend in this field. This study uses the bibliometric method to identify the evolutionary development and recent hotspots of hypertensive nephropathy. The Web of Science Core Collection database was used to extract publications on hypertensive nephropathy from January 2000 to November 2023. CiteSpace was used to capture the patterns and trends from multi-perspectives, including countries/regions, institutions, keywords, and references. In total, 557 publications on hypertensive nephropathy were eligible for inclusion. China (n = 208, 37.34%) was the most influential contributor among all the countries. Veterans Health Administration (n = 19, 3.41%) was found to be the most productive institution. Keyword bursting till now are renal fibrosis, outcomes, and mechanisms which are predicted to be the potential frontiers and hotspots in the future. The top seven references were listed, and their burst strength was shown. A comprehensive overview of the current status and research frontiers of hypertensive nephropathy has been provided through the bibliometric perspective. Recent advancements and challenges in hypertensive nephropathy have been discussed. These findings can offer informative instructions for researchers and scholars.

TMEM16A inhibits renal tubulointerstitial fibrosis via Wnt/ß-catenin signaling during hypertension nephropathy.

BACKGROUND AND OBJECTIVE: Hypertensive nephropathy is the second leading cause of end-stage renal disease, but its underlying pathogenesis remains unclear. Therefore, this study aimed to explore whether transmembrane protein 16 A (TMEM16A), the molecular basis of calcium-activated chloride channels (CaCC), is involved in the development and progression of hypertensive nephropathy. METHODS: In vivo and in vitro experiments were conducted using a hypertensive murine model and human kidney proximal tubular epithelial cells (HK-2 cells), respectively. EXPERIMENTAL RESULTS: The expression of TMEM16A was down-regulated in renal samples of hypertensive nephropathy patients and hypertensive model mice, accompanied by excessive deposition of extracellular matrix proteins (ECM) such as Fibronectin, Laminin, Collagen I and Collagen III, the up-regulation of α-smooth muscle actin (α-SMA) expression, and the decrease of E-cadherin. Overexpression of TMEM16A or knockdown of TMEM16A inhibited or promoted the expression of Wnt/ß-catenin signaling pathway proteins Wnt3a, LRP5 and active ß-catenin in HK-2 cells, preventing the epithelial-to-mesenchymal transition (EMT) of renal tubules, and the synthesis of ECM components. CONCLUSION: In angiotensin II (Ang II)-induced hypertensive nephropathy, TMEM16A was identified as a key player inhibiting the detrimental changes in renal tubules, suggesting a potential avenue for mitigating renal damage in hypertensive nephropathy.

The Impact of Obesity on Kidney Disease: Observational Cohort Study Analyzing 14,492 Kidney Biopsy Cases.

BACKGROUND: The obesity epidemic is associated with the emergence of new kidney diseases including obesity-related glomerulopathy (ORG) and metabolic syndrome-associated disorders. However, the effects of obesity on prevalence and outcome of biopsy-proven kidney disease are not well known. METHODS: We analyzed 14,492 kidney biopsies in 18 hospitals from 1979 to 2018 in Korea. Obesity was defined as a body mass index value of ≥ 30 kg/m². RESULTS: The most common disease was IgA nephropathy (IgAN) in both obese and non-obese participants (33.7% vs. 38.9%). Obesity was associated with a higher risk of focal segmental glomerulosclerosis (FSGS) and hypertensive nephropathy (HT-N) (odds ratio [OR], 1.72, 95% confidence interval [CI], 1.37-2.17; OR, 1.96, 95% CI, 1.21-3.19) and a lower risk of IgAN (OR, 0.74, 95% CI, 0.62-0.88). During the median follow up of 93.1 ± 88.7 months, obesity increased the risk of end-stage kidney disease (ESKD) in patients with IgAN (relative risk [RR], 1.49, 95% CI, 1.01-2.20) and lupus nephritis (LN) (RR, 3.43, 95% CI, 1.36-8.67). Of 947 obese individuals, ORG was detected in 298 (31.5%), and 230 participants had other kidney diseases, most commonly, IgAN (40.9%) followed by diabetic nephropathy (15.2%). Participants with ORG, when combined with other renal diseases, showed higher risks for developing ESKD compared to those with ORG alone (RR, 2.48, 95% CI, 1.09-5.64). CONCLUSION: Obesity is associated with an increased risk of FSGS and HT-N, and also increase the ESKD risk in IgAN and LN patients. ORG in obese participants may have favorable renal outcomes if it occurs alone without any other renal disease.

Cardiovascular and renal diseases in type 2 diabetes patients: 5-year cumulative incidence of the first occurred manifestation and hospitalization cost: a cohort within the French SNDS nationwide claims database.

BACKGROUND: Myocardial infarction (MI), stroke, peripheral arterial disease (PAD), heart failure (HF) and chronic kidney disease (CKD) are common cardiovascular renal diseases (CVRD) manifestations for type 2 diabetes. The objective was to estimate the incidence of the first occurring CVRD manifestation and cumulative hospitalization costs of each CVRD manifestation for type 2 diabetes without CVRD history. METHODS: A cohort study of all type 2 diabetes free of CVRD as of January 1st 2014, was identified and followed-up for 5 years within the French SNDS nationwide claims database. The cumulative incidence of the first occurring CVRD manifestation was estimated using the cumulative incidence function, with death as a competing risk. Cumulative hospitalization costs of each CVRD manifestations were estimated from the perspective of all payers. RESULTS: From 2,079,089 type 2 diabetes without cancer or transplantation, 76.5% were free of CVRD at baseline with a mean age of 65 years, 52% of women and 7% with microvascular complications history. The cumulative incidence of a first CVRD manifestation was 15.3% after 5 years of follow-up with a constant linear increase over time for all CVRD manifestations: The most frequent was CKD representing 40.6% of first occurred CVRD manifestation, followed by HF (23.0%), then PAD (13.5%), stroke (13.2%) and MI (9.7%). HF and CKD together reached about one patient out of ten after 5 years and represented 63.6% of first CVRD manifestations. The 5-year global cost of all CVRD hospitalizations was 3.9 billion euros (B€), i.e. 2,450€ per patient of the whole cohort, with an exponential increase over time for each specific CVRD manifestation. The costliest was CKD (2.0 B€), followed by HF (1.2 B€), then PAD (0.7 B€), stroke (0.6 B€) and MI (0.3 B€). CONCLUSIONS/INTERPRETATION: While MI, stroke and PAD remain classic major risks of complications for CVRD-free type 2 diabetes, HF and CKD nowadays represent individually a higher risk and cost than each of these classic manifestations, and jointly represents a risk and a cost twice as high as these three classic manifestations all together. This should encourage the development of specific HF and CKD preventive strategies.

Cumulative blood pressure load and hypertensive nephropathy in Han Chinese hypertensive patients.

The study aims to assess the relationship between cumulative blood pressure load (cBPL) and the risk of renal function decline in hypertensive patients and determine the blood pressure (BP) threshold required to prevent hypertensive nephropathy. A single-center prospective cohort study was conducted on hypertensive patients. The cBPL was defined as the proportion of area beyond variable BP cutoffs under ambulatory BP monitoring. Renal events were defined as > 25% (minor) or > 50% (major) decline of baseline estimated glomerular filtration rate (eGFR). Cox regression analysis was conducted between cBPL, other ambulatory BP parameters, and renal events. The results revealed a total of 436 Han Chinese hypertensive patients were eligible for enrollment. During an average follow-up period of 5.1 ± 3.3 years, a decline of > 25% and > 50% in eGFR was observed in 77 and eight participants, respectively. Cox regression analysis revealed that cSBPL140 (hazard ratio [HR], 1.102; 95% confidence interval [CI], 1.017-1.193; p = .017), cSBPL130 (HR, 1.076; 95% CI, 1.019-1.137; p = .008), and cSBPL120 (HR, 1.054; 95% CI, 1.010-1.099; p = .015) were independently associated with minor renal events. Similarly, cSBPL140 (HR, 1.228; 95% CI, 1.037-1.455; p = .017), cSBPL130 (HR, 1.189; 95% CI, 1.045-1.354; p = .009), and cSBPL120 (HR, 1.155; 95% CI, 1.039-1.285; p = .008) were independently associated with major renal events. In conclusion, cBPL is associated with renal function decline in hypertensive patients. Minimizing cBPL120 may decrease the risk of hypertensive nephropathy.

Hypermagnesemia is associated with poor outcomes during hospitalization.

BACKGROUND: Hypermagnesemia is one of the vital electrolyte disturbances and is associated with such chronic conditions as cardiovascular, endocrinologic, renal diseases, and malignancy. AIM: This study evaluates the association between hypermagnesemia and clinical course in hospitalized patients. METHODS: This study was conducted at the University of Health Sciences Haseki Training and Research Hospital Internal Medicine Clinic. We evaluated a total of 3850 patients. 2130 patients have met the inclusion criteria were included in the study. Those who were discharged with healing were evaluated as having a good prognosis. Patients who died or were transferred to the intensive care unit (ICU) were defined as having a poor prognosis. We divided the patients' serum magnesium levels into four quartiles and examined the clinical course/conditions of the patients. RESULTS: Of 2130 patients, 1013 (51.9%) were female. The mean age of patients with poor prognoses (69.2 ± 14.9) was higher than those with good prognoses (59.7 ± 19.1). Hypermagnesemia (4th quartile) was detected in 61 (33.9%), and hypomagnesemia (1st quartile) was found in 42 (23.3%) patients out of 180 patients with poor clinical outcomes. It was statistically significant that hypermagnesemia was more common in patients with poor prognoses (p: 0.002). Chronic kidney disease (CKD) was diagnosed in 258 (53.3%) of 484 hypermagnesemia patients. Hypermagnesemia was found to be more common in patients with CKD, which was statistically significant (p: 0.003). CONCLUSIONS: Hypermagnesemia is associated with poor prognosis independent of comorbidities. Besides hypomagnesemia, hypermagnesemia should be considered a critical electrolyte imbalance.

The trend of hypertension-related chronic kidney disease from 1990 to 2019 and its predictions over 25 years: an analysis of the Global Burden of Disease Study 2019.

BACKGROUND: High blood pressure is a key pathogenetic factor that contributes to the deterioration of kidney function. However, the incidence trend of hypertension-related chronic kidney disease (CKD) has rarely been studied; therefore, we aimed to analyze the global, regional, and national patterns, temporal trends as well as burden of hypertension-related CKD. METHODS: We extracted data on hypertension-related CKD from the Global Burden of Disease (GBD) study database, including the incidence, prevalence, disability-adjusted life years (DALYs), and mortality numbers and rates (per 100,000 population) and further described according to year, location, sex, age, and socio-demographic index (SDI). The estimated annual percentage changes (EAPCs) were calculated to assess the variation in incidence, DALYs, and mortality. We used an age-period-cohort (APC) model framework to analyze the underlying trends in prevalence by age, period, and birth cohort. Nordpred APC analysis was performed to predict the future morbidity and mortality of hypertension-related CKD. RESULTS: In 2019, a total of over 1.57 million new hypertension-related CKD cases were reported worldwide, a 161.97% increase from 1990. Compared to 1990, the age-standardized incidence rates (ASIR) increased in all 21 regions in 2019. In all countries and territories except Iceland, the EAPC in ASIR and the lower boundary of its 95% confidence interval (CI) were higher than 0. ASIR, age-standardized prevalence rates (ASPR), age-standardized DALYs rates (ASDR), and age-standardized mortality rates (ASMR) were not identical among countries with different SDI regions in 2019; additionally, ASIR and ASMR were significantly different among sexes in all SDI regions in 2019. The predicted incidence and mortality counts globally continue to increase to 2044, and there is an upward trend in ASIR for both men and women. CONCLUSIONS: Between 1990 and 2019, the ASIR of hypertension-related CKD demonstrated an ascending trend, and according to our projections, it would remain on the rise for the next 25 years. With remarkable global population growth, aging, and an increasing number of patients with hypertension, the burden of disease caused by hypertension-related CKD continues to increase.

Association of physical activity with risk of chronic kidney disease in China: A population-based cohort study.

BACKGROUND: Information on the association between physical activity (PA) and the risk of chronic kidney disease (CKD) is limited. We aimed to explore the associations of total, domain-specific, and intensity-specific PA with CKD and its subtypes in China. METHODS: The study included 475,376 adults from the China Kadoorie Biobank aged 30-79 years during 2004-2008 at baseline. An interviewer-administered questionnaire was used to collect the information about PA, which was quantified as metabolic equivalent of task hours per day (MET-h/day) and categorized into 4 groups based on quartiles. Cox regression was used to analyze the association between PA and CKD risk. RESULTS: During a median follow-up of 12.1 years, 5415 incident CKD cases were documented, including 1159 incident diabetic kidney disease (DKD) cases and 362 incident hypertensive nephropathy (HTN) cases. Total PA was inversely associated with CKD risk, with an adjusted hazard ratio (HR, 95% confidence interval (95%CI)) of 0.83 (0.75-0.92) for incident CKD in the highest quartile of total PA as compared with participants in the lowest quartile. Similar results were observed for risk of DKD and HTN, and the corresponding HRs (95%CIs) were 0.75 (0.58-0.97) for DKD risk and 0.56 (0.37-0.85) for HTN risk. Increased nonoccupational PA, low-intensity PA, and moderate-to-vigorous-intensity PA were significantly associated with a decreased risk of CKD, with HRs (95%CIs) of 0.80 (0.73-0.88), 0.85 (0.77-0.94), and 0.85 (0.76-0.95) in the highest quartile, respectively. CONCLUSION: PA, including nonoccupational PA, low-intensity PA, and moderate-to-vigorous-intensity PA, was inversely associated with the risk of CKD, including DKD, HTN, and other CKD, and such associations were dose dependent.

OTUD1 promotes hypertensive kidney fibrosis and injury by deubiquitinating CDK9 in renal epithelial cells.

Hypertensive renal disease (HRD) contributes to the progression of kidney dysfunction and ultimately leads to end-stage renal disease. Understanding the mechanisms underlying HRD is critical for the development of therapeutic strategies. Deubiquitinating enzymes (DUBs) have been recently highlighted in renal pathophysiology. In this study, we investigated the role of a DUB, OTU Domain-Containing Protein 1 (OTUD1), in HRD models. HRD was induced in wild-type or Otud1 knockout mice by chronic infusion of angiotensin II (Ang II, 1 µg/kg per min) through a micro-osmotic pump for 4 weeks. We found that OTUD1 expression levels were significantly elevated in the kidney tissues of Ang II-treated mice. Otud1 knockout significantly ameliorated Ang II-induced HRD, whereas OTUD1 overexpression exacerbated Ang II-induced kidney damage and fibrosis. Similar results were observed in TCMK-1 cells but not in SV40 MES-13 cells following Ang II (1 µM) treatment. In Ang II-challenged TCMK-1 cells, we demonstrated that OTUD1 bound to CDK9 and induced CDK9 deubiquitination: OTUD1 catalyzed K63 deubiquitination on CDK9 with its Cys320 playing a critical role, promoting CDK9 phosphorylation and activation to induce inflammatory responses and fibrosis in kidney epithelial cells. Administration of a CDK9 inhibitor NVP-2 significantly ameliorated Ang II-induced HRD in mice. This study demonstrates that OTUD1 mediates HRD by targeting CDK9 in kidney epithelial cells, suggesting OTUD1 is a potential target in treating this disease.

OTUD6A in tubular epithelial cells mediates angiotensin II-induced kidney injury by targeting STAT3.

Kidney fibrosis is a prominent pathological feature of hypertensive kidney diseases (HKD). Recent studies have highlighted the role of ubiquitinating/deubiquitinating protein modification in kidney pathophysiology. Ovarian tumor domain-containing protein 6 A (OTUD6A) is a deubiquitinating enzyme involved in tumor progression. However, its role in kidney pathophysiology remains elusive. We aimed to investigate the role and underlying mechanism of OTUD6A during kidney fibrosis in HKD. The results revealed higher OTUD6A expression in kidney tissues of nephropathy patients and mice with chronic angiotensin II (Ang II) administration than that from the control ones. OTUD6A was mainly located in tubular epithelial cells. Moreover, OTUD6A deficiency significantly protected mice against Ang II-induced kidney dysfunction and fibrosis. Also, knocking OTUD6A down suppressed Ang II-induced fibrosis in cultured tubular epithelial cells, whereas overexpression of OTUD6A enhanced fibrogenic responses. Mechanistically, OTUD6A bounded to signal transducer and activator of transcription 3 (STAT3) and removed K63-linked-ubiquitin chains to promote STAT3 phosphorylation at tyrosine 705 position and nuclear translocation, which then induced profibrotic gene transcription in epithelial cells. These studies identified STAT3 as a direct substrate of OTUD6A and highlighted the pivotal role of OTUD6A in Ang II-induced kidney injury, indicating OTUD6A as a potential therapeutic target for HKD.NEW & NOTEWORTHY Ovarian tumor domain-containing protein 6 A (OTUD6A) knockout mice are protected against angiotensin II-induced kidney dysfunction and fibrosis. OTUD6A promotes pathological kidney remodeling and dysfunction by deubiquitinating signal transducer and activator of transcription 3 (STAT3). OTUD6A binds to and removes K63-linked-ubiquitin chains of STAT3 to promote its phosphorylation and activation, and subsequently enhances kidney fibrosis.

Aldosterone and aldosterone synthase inhibitors in cardiorenal disease.

Modulation of the renin-angiotensin-aldosterone system is a foundation of therapy for cardiovascular and kidney diseases. Excess aldosterone plays an important role in cardiovascular disease, contributing to inflammation, fibrosis, and dysfunction in the heart, kidneys, and vasculature through both genomic and mineralocorticoid receptor (MR)-mediated as well as nongenomic mechanisms. MR antagonists have been a key therapy for attenuating the pathologic effects of aldosterone but are associated with some side effects and may not always adequately attenuate the nongenomic effects of aldosterone. Aldosterone is primarily synthesized by the CYP11B2 aldosterone synthase enzyme, which is very similar in structure to other enzymes involved in steroid biosynthesis including CYP11B1, a key enzyme involved in glucocorticoid production. Lack of specificity for CYP11B2, off-target effects on the hypothalamic-pituitary-adrenal axis, and counterproductive increased levels of bioactive steroid intermediates such as 11-deoxycorticosterone have posed challenges in the development of early aldosterone synthase inhibitors such as osilodrostat. In early-phase clinical trials, newer aldosterone synthase inhibitors demonstrated promise in lowering blood pressure in patients with treatment-resistant and uncontrolled hypertension. It is therefore plausible that these agents offer protection in other disease states including heart failure or chronic kidney disease. Further clinical evaluation will be needed to clarify the role of aldosterone synthase inhibitors, a promising class of agents that represent a potentially major therapeutic advance.