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Patients with end-stage renal disease (ESRD) receiving hemodialysis (HD) treatment have a markedly shortened life expectancy in large part owing to cardiovascular disease (CVD), not explained by established risk factors. We tested the hypothesis that therapy with valsartan, an angiotensin receptor blocker and amlodipine, an antioxidant calcium channel blocker will reduce oxidative stress and the plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase. We confirmed that compared with age- and gender-matched healthy controls, ESRD patients have excessive oxidative stress and arginine methylation as indexed by elevated plasma levels of oxidation products of lipids (13-hydroxyoctadecadienoic acid (13-HODE)), thiols (oxidized:reduced glutathione, oxidized glutathione (GSSG):GSH), proteins, and nucleic acids, and the methylation products ADMA and symmetric dimethylarginine (SDMA). We undertook a double blind, crossover study of equi-antihypertensive treatment with amlodipine and valsartan for 6 weeks each to test our hypothesis. Both treatments significantly reduced GSSG:GSH, 8-hydroxy 2-deoxyguanosine, ADMA, and SDMA levels and amlodipine reduced 13-HODE. We conclude that hypertensive patients with ESRD receiving HD have evidence of extensive oxidation of lipids, thiols, proteins, and nucleic acids and methylation of arginine that could contribute to CVD. Many of these changes can be reduced by short-term treatment with amlodipine and valsartan.

Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy Angiotensin I-converting enzyme (ACE) inhibitors reduce angiotensin II formation and induce bradykinin accumulation. Animal studies suggest that bradykinin may play a role for the effects of ACE inhibition on blood pressure and kidney function. Therefore, we compared the renal and hemodynamic effects of specific intervention in the renin-angiotensin system by blockade of the angiotensin II subtype-1 receptor to the effect of ACE inhibition. A randomized, double-blind, cross-over trial was performed in 16 type 1 diabetic patients (10 men), age 42 ± 2 years (mean ± SEM). The study consisted of five periods, each lasting two months. The patients received losartan 50 mg, losartan 100 mg, enalapril 10 mg, enalapril 20 mg, and placebo in random order. At the end of each period, albuminuria, 24-hour blood pressure, and glomerular filtration rate (GFR) were determined. Both doses of losartan and enalapril reduced albuminuria (P < 0.05) and mean arterial blood pressure (MABP; P < 0.05), whereas GFR remained stable. Albuminuria was reduced by 33% (95% CI, 12 to 51) on losartan 50 mg, 44% (95% CI, 26 to 57) on losartan 100 mg, 45% (95% CI, 23 to 61) on enalapril 10 mg, and 59% (95% CI, 39 to 72) on enalapril 20 mg, and MABP fell by 9 ± 2, 8 ± 2, 6 ± 3, and 11 ± 3mm Hg (mean ± SEM), respectively. No significant differences were found between the effects of losartan 100 mg and enalapril 20 mg. HbA1C and sodium intake remained unchanged throughout the study, whereas a significant rise in serum potassium occurred during ACE inhibition. The angiotensin II subtype 1 receptor antagonist, losartan, reduces albuminuria and MABP similar to the effect of ACE inhibition. These results indicate that the reduction in albuminuria and blood pressure during ACE inhibition is primarily caused by interference in the renin-angiotensin system. Our study suggest that losartan represents a valuable new drug in the treatment of hypertension and proteinuria in type 1 diabetic patients with diabetic nephropathy.

Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients. In hypertensive type 2 diabetic patients, treatment with angiotensin-converting enzyme (ACE) inhibitors is associated with a lower incidence of cardiovascular events than those treated with calcium channel-blocking agents. However, the long-term renal effects of ACE inhibitors in these patients remain inconclusive. In 1989, we commenced a placebo-controlled, double-blind, randomized study to examine the anti-albuminuric effects of enalapril versus nifedipine (slow release) in 102 hypertensive, type 2 diabetic patients. These patients have been followed up for a mean trial duration of 5.5 ± 2.2 years. We examined the determinants, including the effect of ACE inhibition on clinical outcomes in these patients. After a six-week placebo-controlled, run-in period, 52 patients were randomized double-blind to receive nifedipine (slow release) and 50 patients to receive enalapril. After the one-year analysis, which confirmed the superior anti-albuminuric effects of enalapril (-54%) over nifedipine (+11%), all patients were continued on their previously assigned treatment with informed consent. They were subdivided into normoalbuminuric (N = 43), microalbuminuric (N = 34), and macroalbuminuric (N = 25) groups based on two of three 24-hour urinary albumin excretion (UAE) measurements during the run-in period. Renal function was shown by the 24-hour UAE, creatinine clearance (CCr), and the regression coefficient of the yearly plasma creatinine reciprocal (β-1/Cr). Clinical endpoints were defined as death, cardiovascular events, and/or renal events (need for renal replacement therapy or doubling of baseline plasma creatinine). In the whole group, patients treated with enalapril were more likely to revert to being normoalbuminuric (23.8 vs. 15.4%), and fewer of them developed macroalbuminuria (19.1 vs. 30.8%) compared with the nifedipine-treated patients (P < 0.05). In the microalbuminuric group, treatment with enalapril (N = 21) was associated with a 13.0% (P < 0.01) reduction in 24-hour UAE compared with a 17.3% increase in the nifedipine group (N = 13). In the macroalbuminuric patients, enalapril treatment (N = 11) was associated with stabilization compared with a decline in renal function in the nifedipine group, as shown by the β-1/Cr (0.65 ± 4.29 vs. -1.93 ± 2.35 1/μmol × 10-3, P < 0.05) after adjustment for baseline values. Compared with the normoalbuminuric and microalbuminuric patients, those with macroalbuminuria had the lowest mean CCr (75.5 ± 24.1 vs. 63.5 ± 21.3 vs. 41.9 ± 18.5 mL/min, P < 0.001) and the highest frequency of clinical events (4.7 vs. 5.9 vs. 52%, P < 0.001). On multivariate analysis, β-1/Cr (R2 = 0.195, P < 0.001) was independently associated with baseline HbA1c (β = -0.285, P = 0.004), whereas clinical outcomes (R2 = 0.176, P < 0.001) were independently related to the mean low-density lipoprotein cholesterol (β = 2.426, P = 0.018), high-density lipoprotein cholesterol (β = -8.797, P = 0.03), baseline UAE (β = 0.002, P = 0.04), and mean CCr during treatment (β = -0.211, P = 0.006). In this prospective cohort analysis involving 102 hypertensive, type 2 diabetic patients with varying degrees of albuminuria followed up for a mean duration of five years, we observed the importance of good metabolic and blood pressure control on the progression of albuminuria and renal function. Treatment with enalapril was associated with a greater reduction in albuminuria than with nifedipine in the entire patient group, and especially in those with microalbuminuria. In the macroalbuminuric patients, the rate of deterioration in renal function was also attenuated by treatment with enalapril.

Chemerin and its receptor, chemokine-like receptor 1 (CmklR1), are associated with chemotaxis, inflammation, and endothelial function, especially in metabolic syndrome, coronary heart disease, and hypertension. In humans, circulating chemerin levels and renal function show an inverse relation. So far, little is known about the potential role of chemerin in hypertensive nephropathy and renal inflammation. Therefore, we determined systemic and renal chemerin levels in 2-kidney-1-clip (2k1c) hypertensive and Thy1.1 nephritic rats, respectively, to explore the correlation between chemerin and markers of renal inflammation and fibrosis. Immunohistochemistry revealed a model-specific induction of chemerin expression at the corresponding site of renal damage (tubular vs. glomerular). In both models, renal expression of chemerin (RT-PCR, Western blot) was increased and correlated positively with markers of inflammation and fibrosis. In contrast, circulating chemerin levels remained unchanged. Taken together, these findings demonstrate that renal chemerin expression is associated with processes of inflammation and fibrosis-related to renal damage. However, its use as circulating biomarker of renal inflammation seems to be limited in our rat models.

Hypertensive nephropathy (HN) is one of the main causes of end-stage renal disease (ESRD), leading to serious morbidity and mortality in hypertensive patients. However, existing treatment for hypertensive nephropathy are still very limited. It has been demonstrated that aerobic exercise has beneficial effects on the treatment of hypertension. However, the underlying mechanisms of exercise in HN remain unclear. The spontaneously hypertensive rats (SHR) were trained for 8 weeks on a treadmill with different exercise prescriptions. We detected the effects of moderate intensity continuous training (MICT) and high intensity interval training (HIIT) on inflammatory response, renal function, and renal fibrosis in SHR. We further investigated the relationship between TLR4 and the NLRC4 inflammasome in vitro HN model. MICT improved renal fibrosis and renal injury, attenuating the inflammatory response by inhibiting TLR4/NF-κB pathway and the activation of NLRC4 inflammasome. However, these changes were not observed in the HIIT group. Additionally, repression of TLR4/NF-κB pathway by TAK-242 inhibited activation of NLRC4 inflammasome and alleviated the fibrosis in Ang II-induced HK-2 cells. MICT ameliorated renal damage, inflammatory response, and renal fibrosis via repressing TLR4/NF-κB pathway and the activation of NLRC4 inflammasome. This study might provide new references for exercise prescriptions of hypertension.

Hypertension constitutes a significant public health concern, characterized by a high incidence and mortality rate. Hypertensive kidney disease is a prevalent complication associated with hypertension and is the second leading cause of end-stage renal disease (ESRD). Renal fibrosis linked to hypertension has emerged as the third leading cause of disease in dialysis patients. Autophagy activity is crucial for maintaining homeostasis, vitality, and physiological function of kidney cells, while also protecting the kidneys from fibrosis. The deficiency of autophagy will increase the sensitivity of the kidney to the damage, leading to impaired renal function, accumulation of damaged mitochondria and more severe of renal fibrosis. However, enhancing autophagy by activating the PI3K/AKT, AMPK, and mTOR pathways, improves podocyte injury and renal pathological changes, and ameliorates renal function. Current clinical interventions aimed at halting or reversing renal fibrosis in hypertensive patients are notably limited in their efficacy. Here, we present Non-lethal Sonodynamic Therapy (NL-SDT), in which ultrasound is used to activate locally sonosensitizers, thereby stimulating the production of reactive oxygen species for the purpose of modulating cell function or fate, as a novel methodology to inhibit progression of hypertensive renal fibrosis. To confirm whether NL-SDT can reduce hypertensive renal fibrosis and its mechanism. The mice model of hypertensive renal fibrosis was established by using osmotic minipumps (Alzet model 2004, Cupertino, CA) equipped with angiotensin-II (Ang II). The pumps were implanted in mice, ensuring constant infusion of Ang II at a dose of 1.0 µg/kg per minute for 4 weeks. The mice were exposed to 0.4 W/cm 2 intensity ultrasonic radiation for 15 min at 4 h post injection of sinoporphyrin sodium (DVDMS) (4 mg/kg) into the caudal vein was repeated weekly for 4 treatments. The kidney from mice was stained with masson’s trichrome staining for collagen fiber expression, while alpha-smooth muscle actin (α-SMA) expression was determined via immunohistochemical staining. The protein levels of fibrosis parameters (α-SMA, collagen I, vimentin), pathway-related proteins (PI3K, AKT, mTORC1) and autophagy-related protein LC3B were determined using western blotting. Intracellular reactive oxygen species (ROS) levels were detected using DCFH-DA probe. Immunofluorescence was also used to observe the expression of α-SMA and E-cadherin in cells. Pathway-related protein inhibitors (the autophagy-related inhibitor 3-methyladenine (3-MA), chloroquine (CQ), ROS inhibitor N-acetyl-L-cysteine (NAC) were applied, and autophagosome changes were observed under transmission electron microscopy. Immunofluorescence was used to observe LC3 spot formation within cells. We obtained the following results via animal and cellular research. In vivo, (1) The collagen area of renal tissue was increased significantly in Ang II group (50.6%). The positive expression of α-SMA was increased significantly (37.8%). (2) The collagen area decreased after NL-SDT treatment (34.8%). The expression of α-SMA was decreased too (48.9%). The expression of LC3B increased in NL-SDT group. (3) The effect of NL-SDT on reducing renal fibrosis can be changed by rapamycin and CQ. In vitro. (1) The expression of α-SMA, collagen I and vimentin were increased significantly in TGF-β1-induced NRK-52E cells. (2) The increase of autophagosomes was observed in TGF-β1-induced NRK-52E cells after NL-SDT. The levels of ROS were increased after NL-SDT (24.8%). The effect of NL-SDT on autophagy was reversed after administration of NAC. The expression of PI3K, P-AKT and P-mTORC1 was decreased in TGF-β1-induced NRK-52E cells after NL-SDT. NL-SDT inhibited the transition of epithelial cells into myofibroblasts by activating PI3K-AKT-mTORC1-autophagy pathway in TGF-β1-induced NRK-52E cells. (3) The administration of the pathway inhibitors showed a reciprocal effect on NL-SDT-inhibited epithelial-mesenchymal transition (EMT). (1) NL-SDT reduced blood pressure temporarily in mice model of hypertensive renal fibrosis induced by Ang II. (2) NL-SDT alleviated renal fibrosis in mice model of hypertensive renal fibrosis induced by Ang II. (3) NL-SDT promoted autophagy by inhibiting PI3K-AKT-mTORC1 signaling pathway and alleviated renal fibrosis in mice model of hypertensive renal fibrosis induced by Ang II. NL-SDT is a non-invasive and efficacious regimen to inhibit renal fibrosis. It may be a new approach for clinical treatment of renal fibrosis, delaying or reducing the occurrence of ESRD.

Macrophage activation has been shown to play an essential role in renal fibrosis and dysfunction in hypertensive chronic kidney disease. Dectin-1 is a pattern recognition receptor that is also involved in chronic noninfectious diseases through immune activation. However, the role of Dectin-1 in Ang II-induced renal failure is still unknown. In this study, we found that Dectin-1 expression on CD68 + macrophages was significantly elevated in the kidney after Ang II infusion. We assessed the effect of Dectin-1 on hypertensive renal injury using Dectin-1-deficient mice infused by Angiotensin II (Ang II) at 1000 ng/kg/min for 4 weeks. Ang II-induced renal dysfunction, interstitial fibrosis, and immune activation were significantly attenuated in Dectin-1-deficient mice. A Dectin-1 neutralizing antibody and Syk inhibitor (R406) were used to examine the effect and mechanism of Dectin-1/Syk signaling axle on cytokine secretion and renal fibrosis in culturing cells. Blocking Dectin-1 or inhibiting Syk significantly reduced the expression and secretion of chemokines in RAW264.7 macrophages. The in vitro data showed that the increase in TGF-β1 in macrophages enhanced the binding of P65 and its target promotor via the Ang II-induced Dectin-1/Syk pathway. Secreted TGF-β1 caused renal fibrosis in kidney cells through Smad3 activation. Thus, macrophage Dectin-1 may be involved in the activation of neutrophil migration and TGF-β1 secretion, thereby promoting kidney fibrosis and dysfunction.

Pharmacological inhibition of the proximal tubular sodium-glucose linked cotransporter-2 (SGLT2) leads to glycosuria in both diabetic and non-diabetic settings. As a consequence of their ability to modulate tubuloglomerular feedback, SGLT2 inhibitors, like agents that block the renin-angiotensin system, reduce intraglomerular pressure and single nephron GFR, potentially affording renoprotection. To examine this further we administered the SGLT2 inhibitor, dapagliflozin, to 5/6 (subtotally) nephrectomised rats, a model of progressive chronic kidney disease (CKD) that like CKD in humans is characterised by single nephron hyperfiltration and intraglomerular hypertension and where angiotensin converting enzyme inhibitors and angiotensin receptor blockers are demonstrably beneficial. When compared with untreated rats, both sham surgery and 5/6 nephrectomised rats that had received dapagliflozin experienced substantial glycosuria. Nephrectomised rats developed hypertension, heavy proteinuria and declining GFR that was unaffected by the administration of dapagliflozin. Similarly, SGLT2 inhibition did not attenuate the extent of glomerulosclerosis, tubulointerstitial fibrosis or overexpression of the profibrotic cytokine, transforming growth factor-ß1 mRNA in the kidneys of 5/6 nephrectomised rats. While not precluding beneficial effects in the diabetic setting, these findings indicate that SGLT2 inhibition does not have renoprotective effects in this classical model of progressive non-diabetic CKD.

Hypertensive nephropathy (HN), caused by long-term poorly controlled hypertension, is the second common cause of end-stage renal disease after diabetes mellitus, but the pathogenesis of HN is unclear. The purpose of this study was to identify the biological pathways involved in the progression of HN and bile acid (BA)-related biomarkers, and to analyze the role of bile acids in HN. Download gene microarray data from Gene Expression Omnibus. Differentially expressed genes (DEGs) associated with HN were identified, and then DEGs were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. A protein–protein interaction (PPI) network was established using DEGs to identify BA-related hub genes in combination with bile acid identical targets. An animal model of early hypertensive nephropathy was established using SHR and the concentrations of 39 bile acids were measured quantitatively in the renal cortex to screen for significantly different concentrations and to analyze the correlation between bile acid concentrations and blood pressure. A total of 398 DEGs were screened. The results of enrichment analysis identified multiple biological pathways associated with hypertension, nephropathy and bile acids. Combining PPI network and bile acid-related targets, three BA-related hub genes (APOE, ALB, SERPINA1) were identified. Quantitative analysis of bile acids revealed significant differences in the concentrations of seven bile acids (DCA, CDCA, UDCA, UCA, CA, TDCA, TCDCA). The concentrations of these bile acids showed a positive correlation with blood pressure values in SHR, with CA, DCA and TDCA showing a stronger correlation and specificity with blood pressure in SHR. Three BA-related hub genes (APOE, ALB, SERPINA1) may be involved in the early stages of HN. The concentrations of multiple bile acids were significantly elevated in the early stages of HN, with CA, DCA and TDCA being more correlated and specific with blood pressure and having higher diagnostic value. These BA-related hub genes and BAs may be involved in disease progression in the early stages of HN.

MicroRNAs (miRNAs) are endogenous short (20–22 nucleotides) non-coding RNA molecules that mediate gene expression. This is an important regulatory mechanism to modulate fundamental cellular processes such as differentiation, proliferation, death, metabolism, and pathophysiology of many diseases. The miRNA expression profile of the kidney differs greatly from that of other organs, as well as between the different regions in the kidney. In kidneys, miRNAs are indispensable for development and homeostasis. In this review, we explore the involvement of miRNAs in the regulation of blood pressure, hormone, water, and ion balance pertaining to kidney homeostasis. We also highlight their importance in renal pathophysiology, such as in polycystic disease, diabetic nephropathy, nephrogenic diabetes insipidus, hypertension, renal cancer, and kidney fibrosis (epithelial–mesenchymal transition). In addition, we highlight the need for further investigations on miRNA-based studies in the development of diagnostic, prognostic, and therapeutic tools for renal diseases.