Search

Mineralocorticoid excess commonly leads to hypertension (HTN) and kidney disease. In our study, we used single-cell expression and chromatin accessibility tools to characterize the mineralocorticoid target genes and cell types. We demonstrated that mineralocorticoid effects were established through open chromatin and target gene expression, primarily in principal and connecting tubule cells and, to a lesser extent, in segments of the distal convoluted tubule cells. We examined the kidney-protective effects of steroidal and nonsteroidal mineralocorticoid antagonists (MRAs), as well as of amiloride, an epithelial sodium channel inhibitor, in a rat model of deoxycorticosterone acetate, unilateral nephrectomy, and high-salt consumption-induced HTN and cardiorenal damage. All antihypertensive therapies protected against cardiorenal damage. However, finerenone was particularly effective in reducing albuminuria and improving gene expression changes in podocytes and proximal tubule cells, even with an equivalent reduction in blood pressure. We noted a strong correlation between the accumulation of injured/profibrotic tubule cells expressing secreted posphoprotein 1 (Spp1), Il34, and platelet-derived growth factor subunit b (Pdgfb) and the degree of fibrosis in rat kidneys. This gene signature also showed a potential for classifying human kidney samples. Our multiomics approach provides fresh insights into the possible mechanisms underlying HTN-associated kidney disease, the target cell types, the protective effects of steroidal and nonsteroidal MRAs, and amiloride.

Recently, we reported that the early progression of renal injury in obese Dahl salt-sensitive leptin receptor mutant (SS LepR mutant) rats was associated with increased macrophage inflammatory protein 3- α (MIP3 α ) expression prior to puberty. Therefore, this study tested the hypothesis that MIP3 α plays a role in recruiting immune cells, thereby triggering renal inflammation and early progressive renal injury in SS LepR mutant rats prior to puberty. Four-week-old Dahl salt-sensitive (SS) and SS LepR mutant rats either served as control (IgG; intraperitoneal, every other day) or received MIP3 α -neutralizing antibody (MNA; 100 µg/kg) for 4 weeks. MNA reduced circulating and renal MIP3 α levels and proinflammatory immune cells by 50%. Although MNA treatment did not affect blood glucose and plasma cholesterol levels, MNA markedly decreased insulin resistance and triglyceride levels in SS LepR mutant rats. We observed no differences in mean arterial pressure (MAP) between SS and SS LepR mutant rats, and MNA had no effect on MAP in either strain. Proteinuria was significantly increased in SS LepR mutant rats versus SS rats over the course of the study. Treatment with MNA markedly decreased proteinuria in SS LepR mutant rats while not affecting SS rats. Also, MNA decreased glomerular and tubular injury and renal fibrosis in SS LepR mutant rats while not affecting SS rats. Overall, these data indicate that MIP3 α plays an important role in renal inflammation during the early progression of renal injury in obese SS LepR mutant rats prior to puberty. These data also suggest that MIP3 α may be a novel therapeutic target to inhibit insulin resistance and prevent progressive proteinuria in obese children. SIGNIFICANCE STATEMENT: Childhood obesity is increasing at an alarming rate and is now being associated with renal disease. Although most studies have focused on the mechanisms of renal injury associated with adult obesity, few studies have examined the mechanisms of renal injury involved during childhood obesity. In the current study, we observed that the progression of renal injury in obese Dahl salt-sensitive leptin receptor mutant rats was associated with an increase in MIP3 α , a chemokine, before puberty, and inhibition of MIP3 α markedly reduced renal injury., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

The present study examined whether development of renal injury in the nondiabetic obese Dahl salt-sensitive leptin receptor mutant (SS LepR mutant) strain is associated with elevations in glomerular filtration rate and renal lipid accumulation. Baseline mean arterial pressure at 6 wk of age was similar between Dahl salt-sensitive wild-type (SS WT ) and SS LepR mutant rats. However, by 18 wk of age, the SS LepR mutant strain developed hypertension, while the elevation in mean arterial pressure was not as severe in SS WT rats (192 ± 4 and 149 ± 6 mmHg, respectively). At baseline, proteinuria was fourfold higher in SS LepR mutant than SS WT rats and remained elevated throughout the study. The early development of progressive proteinuria was associated with renal hyperfiltration followed by a decline in renal function over the course of study in the SS LepR mutant compared with SS WT rats. Kidneys from the SS LepR mutant strain displayed more glomerulosclerosis and glomerular lipid accumulation than SS WT rats. Glomeruli were isolated from the renal cortex of both strains at 6 and 18 wk of age, and RNA sequencing was performed to identify genes and pathways driving glomerular injury. We observed significant increases in expression of the influx lipid transporters, chemokine (C-X-C motif) ligand 16 (Cxcl16) and scavenger receptor and fatty acid translocase (Cd36), respectively, and a significant decrease in expression of the efflux lipid transporter, ATP-binding cassette subfamily A member 2 ( Abca2 ; cholesterol efflux regulatory protein 2), in SS LepR mutant compared with SS WT rats at 6 and 18 wk of age, which were validated by RT-PCR analysis. These data suggest an association between glomerular hyperfiltration and glomerular lipid accumulation during the early development of proteinuria associated with obesity.

Objective: To develop the missing link between hyperuricemia and hypertension., Methods: The study was conducted in Department of Biochemistry in collaboration with Nephrology Unit of Internal Medicine Department. Hypertension was defined according to blood pressure readings by definitions of the Seventh Report of the Joint National Committee. Totally 205 newly diagnosed and untreated essential hypertensive cases and age-sex matched normotensive controls were enrolled in the study. The potential confounding factors of hyperuricemia and hypertension in both cases and controls were controlled. Uric acid levels in all participants were analyzed., Results: Renal function between newly diagnosed hypertensive cases and normotensive healthy controls were adjusted. The mean serum uric acid observed in newly diagnosed hypertensive cases and in normotensive healthy controls were (290.05±87.05) μmol/L and (245.24±99.38) μmol/L respectively. A total of 59 (28.8%) participants of cases and 28 (13.7%) participants of controls had hyperuricemia (odds ratio 2.555 (95% CI: 1.549-4.213), P<0.001)., Conclusions: The mean serum uric acid levels and number of hyperuricemic subjects were found to be significantly higher in cases when compared to controls., (Copyright © 2014 Asian Pacific Tropical Biomedical Magazine. Published by Elsevier B.V. All rights reserved.)

L7674 --> 968.3 --> Hypertension affects 108 million in the United States, which is more common in African American (AA) population (54%). Several Genome‐Wide Association Studies (GWAS) showed a strong association between the apolipoprotein1 (apol1) gene and hypertension in AA adults. Nearly 45% of AAs carry a coding variant of the APOL1 gene either G1APOL1 or G2APOL1. The disease phenotypes associated with APOL1 RV are dependent on the cell type‐specific expression and toxicity of APOL1. Recently, we have reported that APOL1 is highly expressed in endothelial cells (EC) of the human kidneys using single‐cell analysis, single nuclei analysis, and in‐situ hybridization. People who carry G1 or G2 APOL1 RV have a high risk of chronic kidney disease and hypertensive kidney disease. However, the direct role of APOL1 in the development of hypertension and hypertensive kidney disease is clear. Therefore, the objective of the current study was to examine the role of endothelial‐specific inducible G2APOL1 risk variants in the development of hypertension and hypertensive kidney disease. To understand the role of APOL1 in endothelial cells, we generated mice with endothelial‐specific inducible expression of APOL1 (EC/G2‐APOL1) by crossing the TRE‐G2APOL1 mice with the Cdh5tTA animals. Cadherin 5 (VE‐cadherin or endothelial cadherin) is an endothelial‐specific gene, removal of doxycycline from the diet led to a significant expression of APOL1 in different vascular beds such as the lung, heart, and kidney, which was confirmed both by in situ hybridization and qRT‐PCR. After collecting the baseline data, we performed UNX surgery on both WT control and Cdh5tTA/TRE‐G2APOL1 five‐week‐old mice and kept them in 4% salt diet for 12 weeks after UNX surgery. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) (measured by tail‐cuff method) were significantly higher in Cdh5tTA/TRE‐G2APOL1 mice compared to control WT mice after 6 weeks of UNX surgery on a high salt diet. The significantly higher blood pressure in Cdh5tTA/TRE‐G2APOL1 mice was further associated with the increased urinary albumin/creatinine ratio and renal fibrosis. Interestingly, the blood pressure parameters SBP, DBP, and MAP were significantly reduced on STING, NLRP3, and gasdermin knock‐out mice on Cdh5tTA/TRE‐G2APOL1 background compared to Cdh5tTA/TRE‐G2APOL1 mice upon UNX‐surgery and 4% salt diet. Furthermore, the expression of the transcript of the mitochondrial gene including COX1, COX2, ATP6, and ND6 in the cytoplasm from kidney tissue obtained from Cdh5tTA/TRE‐G2APOL1 mice was significantly higher compared to control‐WT, which indicate that mitochondrial damage and leakage of the mitochondrial gene into the cytoplasm take place in the Cdh5tTA/TRE‐G2APOL1 mice upon UNX‐surgery and 4% salt‐diet. Therefore, EC specific apol1 gene induces mitochondrial damage, upregulates inflammasome and cGAS‐STING pathway to develop hypertension leading to hypertensive kidney disease. This project was supported by DK105821. [ABSTRACT FROM AUTHOR]

Background: Microalbuminuria in hypertension has been described as an early sign of kidney damage and a predictor for end stage renal disease and cardiovascular disease. Thus, it is of great importance to study urinary albumin creatinine ratio and progression of kidney disease in hypertensive patients. Aims: The present study was undertaken to find out the prevalence and association of microalbuminuria in newly diagnosed essential hypertension. Materials and Methods: Newly diagnosed essential hypertensive cases (n = 106) and normotensive controls (n = 106) were enrolled. Hypertension was defined according to Joint national committee-VII definitions. Microalbuminuria was measured using an U-Albumin (NycoCard, Norway) and adjusted for urine creatinine. Descriptive statistics and testing of hypothesis were used for the analysis using SPSS 16 software. Results: 51.88% of hypertension cases and 13.2% of normotensive controls had microalbuminuria in total population (odds ratio 7.086, P-value <0.001). 46.67% of cases and 12.08% of controls had microalbuminuria in male population (odds ratio 6.375, P-value <0.001). Similarly, 58.7% of cases and 14.58% of controls had microalbuminuria in female population (odds ratio 8.32, P-value <0.001). Conclusions: By showing strong association between microalbuminuria and hypertension, our findings suggest that microalbuminuria could be a useful marker to assess risk management of cardiovascular disease and renal disease. [ABSTRACT FROM AUTHOR]