scholarly journals Jian-Pi-Yi-Shen Formula Alleviates Chronic Kidney Disease in Two Rat Models by Modulating QPRT/NAD+/SIRT3/Mitochondrial Dynamics Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Xinhui Liu ◽  
Siqi Liu ◽  
Bing Zhang ◽  
Denggui Luo ◽  
Shiying Huang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Interstitial Fibrosis ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Periodic Acid ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tubular Atrophy ◽  
Rat Models ◽  
Matrix Deposition

Objective. Jian-Pi-Yi-Shen formula (JPYSF) is a traditional Chinese herbal decoction and has been used for treating chronic kidney disease (CKD) in clinics for decades. However, the potential mechanisms have not been fully elucidated. This study was designed to test the efficacy of JPYSF in treating CKD and explore the underlying mechanism. Methods. Two CKD rat models were established by 5/6 nephrectomy (5/6 Nx) and feeding with adenine-containing feed, respectively. The intervention dose of JPYSF was 10.89 g/kg/d by gastric irrigation. Renal function was assessed by serum creatinine (Scr) and blood urea nitrogen (BUN). Periodic acid-Schiff (PAS) and Masson’s trichrome staining were used to evaluate renal histopathological changes. The levels of nicotinamide adenine dinucleotide (NAD+) were measured by using the enzyme-linked immunosorbent assay kit. The proteins expressions of renal fibrosis, quinolinate phosphoribosyltransferase (QPRT), sirtuin 3 (SIRT3), and mitochondrial dynamics were determined and quantified by Western blot analysis. Results. The results show that administration of JPYSF significantly lowered Scr and BUN levels, improved renal tubular atrophy and interstitial fibrosis, and decreased renal extracellular matrix deposition in two CKD rat models. In addition, CKD rats exhibited suppressed QPRT/NAD+/SIRT3 signal, increased mitochondrial fission, and decreased mitochondrial fusion. JPYSF treatment promoted QPRT/NAD+/SIRT3 signal and restored mitochondrial fission/fusion balance. Conclusion. In conclusion, administration of JPYSF effectively alleviated CKD progression in two rat models, which may be related with regulation of the QPRT/NAD+/SIRT3/mitochondrial dynamics pathway.

scholarly journals Huangqi-Danshen Decoction Ameliorates Adenine-Induced Chronic Kidney Disease by Modulating Mitochondrial Dynamics

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Xinhui Liu ◽  
Shiying Huang ◽  
Fochang Wang ◽  
Lin Zheng ◽  
Jiandong Lu ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Interstitial Fibrosis ◽  
Mitochondrial Dynamics ◽  
Smooth Muscle Actin ◽  
Periodic Acid ◽  
Public Health Problem ◽  
High Morbidity ◽  
Tubular Atrophy ◽  
Periodic Acid Schiff

Chronic kidney disease (CKD) is a leading public health problem with high morbidity and mortality. However, the therapies remain limited. Traditional Chinese medicine (TCM) has been used for treating kidney disease for thousands of years and is an effective alternative treatment for CKD patients in China and other Asian countries. In the present study, we aimed to investigate the effect and mechanism of Huangqi-Danshen decoction (HDD), a TCM herbal decoction, on treating CKD. CKD rat model was induced by adding 0.75% adenine to the diet for 4 weeks. HDD extract was administrated orally to CKD rats at the dose of 4.7 g/kg/d for consecutive 4 weeks in adenine-induced CKD rats. Kidney function was evaluated by the levels of serum creatinine (Scr) and blood urea nitrogen (BUN). The pathological changes of kidney tissues were observed by periodic acid-Schiff (PAS) and Masson’s trichrome staining. The proteins expression of renal fibrosis and mitochondrial dynamics were determined and quantified by Western blot analysis. CKD rats showed obvious decline in renal function as evidenced by increased levels of Scr and BUN, which were blunted by HDD treatment. HDD could also improve tubular atrophy and interstitial fibrosis of CKD rats. Moreover, HDD downregulated fibronectin, type IV collagen, and α-smooth muscle actin expression in CKD rats. Furthermore, mitochondrial dynamics was disturbed in CKD rats, which manifested as increased mitochondrial fission and decreased mitochondrial fusion. HDD treatment restored mitochondrial dynamics in CKD rats by repressing dynamin-related protein 1 and Mid 49/51 expression, promoting mitofusin 2 expression, and suppressing optic atrophy 1 proteolysis. In conclusion, HDD could significantly retard CKD progression through modulating mitochondrial dynamics.

scholarly journals Cellular Mechanisms of Tissue Fibrosis. 3. Novel mechanisms of kidney fibrosis

2013 ◽  
Vol 304 (7) ◽  
pp. C591-C603 ◽  
Author(s):  
Gabriela Campanholle ◽  
Giovanni Ligresti ◽  
Sina A. Gharib ◽  
Jeremy S. Duffield
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Interstitial Fibrosis ◽  
Kidney Injury ◽  
Innate Immune ◽  
Cellular Mechanisms ◽  
Tubular Atrophy ◽  
Kidney Fibrosis ◽  
Capillary Rarefaction ◽  
Peritubular Capillaries

Chronic kidney disease, defined as loss of kidney function for more than three months, is characterized pathologically by glomerulosclerosis, interstitial fibrosis, tubular atrophy, peritubular capillary rarefaction, and inflammation. Recent studies have identified a previously poorly appreciated, yet extensive population of mesenchymal cells, called either pericytes when attached to peritubular capillaries or resident fibroblasts when embedded in matrix, as the progenitors of scar-forming cells known as myofibroblasts. In response to sustained kidney injury, pericytes detach from the vasculature and differentiate into myofibroblasts, a process not only causing fibrosis, but also directly contributing to capillary rarefaction and inflammation. The interrelationship of these three detrimental processes makes myofibroblasts and their pericyte progenitors an attractive target in chronic kidney disease. In this review, we describe current understanding of the mechanisms of pericyte-to-myofibroblast differentiation during chronic kidney disease, draw parallels with disease processes in the glomerulus, and highlight promising new therapeutic strategies that target pericytes or myofibroblasts. In addition, we describe the critical paracrine roles of epithelial, endothelial, and innate immune cells in the fibrogenic process.

scholarly journals Urinary chemokine C-X-C motif ligand 16 and endostatin as predictors of tubulointerstitial fibrosis in patients with advanced diabetic kidney disease

2019 ◽  
Author(s):  
Yu Ho Lee ◽  
Ki Pyo Kim ◽  
Sun-Hwa Park ◽  
Dong-Jin Kim ◽  
Yang-Gyun Kim ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Interstitial Fibrosis ◽  
Renal Outcome ◽  
Enzyme Linked Immunosorbent Assay ◽  
Glomerular Injury ◽  
Tubular Atrophy ◽  
Diabetic Kidney ◽  
Cytokines And Chemokines ◽  
Pathologic Features

Abstract Background Interstitial fibrosis and tubular atrophy (IFTA) is a well-recognized risk factor for poor renal outcome in patients with diabetic kidney disease (DKD). However, a noninvasive biomarker for IFTA is currently lacking. The purpose of this study was to identify urinary markers of IFTA and to determine their clinical relevance as predictors of renal prognosis. Methods Seventy patients with biopsy-proven isolated DKD were enrolled in this study. We measured multiple urinary inflammatory cytokines and chemokines by multiplex enzyme-linked immunosorbent assay in these patients and evaluated their association with various pathologic features and renal outcomes. Results Patients enrolled in this study exhibited advanced DKD at the time of renal biopsy, characterized by moderate to severe renal dysfunction [mean estimated glomerular filtration rate (eGFR) 36.1 mL/min/1.73 m2] and heavy proteinuria (mean urinary protein:creatinine ratio 7.8 g/g creatinine). Clinicopathologic analysis revealed that higher IFTA scores were associated with worse baseline eGFR (P < 0.001) and poor renal outcome (P = 0.002), whereas glomerular injury scores were not. Among measured urinary inflammatory markers, C-X-C motif ligand 16 (CXCL16) and endostatin showed strong correlations with IFTA scores (P = 0.001 and P < 0.001, respectively), and patients with higher levels of urinary CXCL16 and/or endostatin experienced significantly rapid renal progression compared with other patients (P < 0.001). Finally, increased urinary CXCL16 and endostatin were independent risk factors for poor renal outcome after multivariate adjustments (95% confidence interval 1.070–3.455, P = 0.029). Conclusions Urinary CXCL16 and endostatin could reflect the degree of IFTA and serve as biomarkers of renal outcome in patients with advanced DKD.

scholarly journals Rhubarb Enema Decreases Circulating Trimethylamine N-Oxide Level and Improves Renal Fibrosis Accompanied With Gut Microbiota Change in Chronic Kidney Disease Rats

2021 ◽  
Vol 12 ◽  
Author(s):  
Chunlan Ji ◽  
Yin Li ◽  
Yenan Mo ◽  
Zhaoyu Lu ◽  
Fuhua Lu ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Intestinal Microbiota ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Underlying Mechanism ◽  
Uremic Toxins ◽  
16S Rrna Sequence ◽  
Tubular Atrophy ◽  
The Impact

Objectives: Trimethylamine N-oxide (TMAO), a metabolic product of gut flora, is increased in chronic kidney disease (CKD) subjects and is recognized as one type of uremic toxins which is associated with poor cardiovascular outcomes and kidney function loss. Previous studies have suggested that rhubarb enema could reduce circulating uremic toxins such as urea, creatinine, and indoxyl sulfate and also regulate the intestinal microbiota. However, whether rhubarb enema retards kidney dysfunction by reducing circulating TMAO and its underlying mechanism, are still unclear. The present study aims to investigate the impact of rhubarb enema on TMAO and its precursors, as well as on the intestinal microbiota in 5/6 nephrectomized (5/6Nx) CKD rats.Design: Rats in the treatment groups were given rhubarb enema after modeling. At the end of the study, blood, feces, and kidney tissues were collected and processed for biochemical analyses, histological and western blot analyses, 16S rRNA sequence and untargeted metabolomic analyses.Results: Rhubarb enema reduced serum TMAO and trimethylamine (TMA) levels, inhibited the expression of inflammatory markers (interleukin-6, tumor necrosis factor α and Interferon-γ) and alleviated tubular atrophy, monocyte infiltration and interstitial fibrosis in 5/6Nx CKD rats. Moreover, rhubarb enema significantly increased the abundance of some symbiotic bacteria and probiotics, while reduced the abundance of some potential pathogens at the genus level. In addition, Spearman’s correlation analysis revealed that lachnospiraceae and romboutsia were positively correlated with TMAO.Conclusion: Rhubarb enema decreases circulating TMAO level and improves renal fibrosis in 5/6Nx CKD rats, which may be related to the regulation of intestinal microbial community.

scholarly journals Follistatin-Like-1 (FSTL1) Is a Fibroblast-Derived Growth Factor That Contributes to Progression of Chronic Kidney Disease

2021 ◽  
Vol 22 (17) ◽  
pp. 9513
Author(s):  
Nicholas A. Maksimowski ◽  
Xuewen Song ◽  
Eun Hui Bae ◽  
Heather Reich ◽  
Rohan John ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Interstitial Fibrosis ◽  
In Silico Analysis ◽  
Mrna Levels ◽  
Tubular Atrophy ◽  
Induced Apoptosis ◽  
Silico Analysis ◽  
Clinical Disease Progression

Our understanding of the mechanisms responsible for the progression of chronic kidney disease (CKD) is incomplete. Microarray analysis of kidneys at 4 and 7 weeks of age in Col4a3-/- mice, a model of progressive nephropathy characterized by proteinuria, interstitial fibrosis, and inflammation, revealed that Follistatin-like-1 (Fstl1) was one of only four genes significantly overexpressed at 4 weeks of age. mRNA levels for the Fstl1 receptors, Tlr4 and Dip2a, increased in both Col4a-/- mice and mice subjected to unilateral ureteral obstruction (UUO). RNAscope® (Advanced Cell Diagnostics, Newark CA, USA) localized Fstl1 to interstitial cells, and in silico analysis of single cell transcriptomic data from human kidneys showed Fstl1 confined to interstitial fibroblasts/myofibroblasts. In vitro, FSTL1 activated AP1 and NFκB, increased collagen I (COL1A1) and interleukin-6 (IL6) expression, and induced apoptosis in cultured kidney cells. FSTL1 expression in the NEPTUNE cohort of humans with focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), and IgA nephropathy (IgAN) was positively associated with age, eGFR, and proteinuria by multiple linear regression, as well as with interstitial fibrosis and tubular atrophy. Clinical disease progression, defined as dialysis or a 40 percent reduction in eGFR, was greater in patients with high baseline FSTL1 mRNA levels. FSTL1 is a fibroblast-derived cytokine linked to the progression of experimental and clinical CKD.

scholarly journals Anti-Inflammatory, Antioxidant, and Antifibrotic Effects of Kefir Peptides on Salt-Induced Renal Vascular Damage and Dysfunction in Aged Stroke-Prone Spontaneously Hypertensive Rats

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 790 ◽  
Author(s):  
Yu-Hsuan Chen ◽  
Hsiao-Ling Chen ◽  
Hueng-Chuen Fan ◽  
Yu-Tang Tung ◽  
Chia-Wen Kuo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Dysfunction ◽  
Renal Damage ◽  
Protective Agent ◽  
Tubular Atrophy ◽  
Spontaneously Hypertensive ◽  
Matrix Deposition ◽  
Anti Inflammatory

The increased prevalence of renal dysfunction and chronic kidney disease (CKD) and the high costs and poor outcomes of treatment are a significant health issue. The consequence of chronic high blood pressure is the increased prevalence of target organ end-stage renal disease, which has been proven to be a strong independent risk factor for adverse cardiovascular disease. A previous study showed that kefir products have anti-inflammatory and anti-hypertensive activities and immunological modulation functions. However, no data regarding the beneficial effects of kefir peptides (KPs) on salt-induced renal damage or related kidney diseases are available. In this study, KPs were orally administered to aged salt-induced stroke-prone spontaneously hypertensive (SHRSP) rats, and the effects of KPs against inflammation and oxidative stress and their ability to protect against renal dysfunction were evaluated. Fifty-five-week-old SHRSP rats under induction with 1% NaCl in drinking water for 4 weeks showed multiple renal injuries with increased renal inflammation, fibrosis, oxidative stress, tubular atrophy, and glomerulosclerosis. In contrast, oral gavage with KPs reduced the urine protein to creatinine (UPC) ratio, the fractional excretion of electrolytes (FeNa and FeCl), extracellular matrix deposition, and the interstitial fibrotic α-smooth muscle actin (α-SMA) levels in salt-induced SHRSP rats. The renal infiltration of inflammatory cells; the release of monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), endothelin-1 (ET-1), and the cytokine nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) and transforming growth factor-β (TGF-β); the reactive oxygen species (ROS) levels; and histopathological lesions were also decreased in salt-induced SHRSP rats. Furthermore, KP treatment significantly increased the renal superoxide dismutase (SOD) activity and the glomerular filtration rate (GFR), which exerted potent protection against salt-induced chronic kidney disease in SHRSP rats. The results of this study suggest that KPs ameliorate salt-induced renal damage, tubular atrophy, and glomerular dysfunction through anti-inflammatory, antioxidative stress, and antifibrotic activities, and might be a promising protective agent against high salt-induced renovascular-related diseases.

scholarly journals Lithium-Associated Kidney Microcysts

2008 ◽  
Vol 8 ◽  
pp. 828-829 ◽  
Author(s):  
Jennifer Tuazon ◽  
David Casalino ◽  
Ehteshamuddin Syed ◽  
Daniel Batlle
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Mr Imaging ◽  
Interstitial Fibrosis ◽  
Renal Cysts ◽  
Lithium Therapy ◽  
Tubular Atrophy ◽  
Advanced Chronic Kidney Disease ◽  
Tubulointerstitial Nephropathy

Long-term lithium therapy is associated with impairment in concentrating ability and, occasionally, progression to advanced chronic kidney disease from tubulointerstitial nephropathy. Biopsy findings in patients with lithium-induced chronic tubulointerstitial nephropathy include tubular atrophy and interstitial fibrosis interspersed with tubular cysts and dilatations. Recent studies have shown that cysts are seen in 33––62.5% of the patients undergoing lithium therapy. MR imaging is highly capable of defining renal morphological features and has been demonstrated to be superior to US and CT scan for the visualization of small renal cysts. The microcysts are found in both cortex and medulla, particularly in the regions with extensive atrophy and fibrosis, and can be multiple and bilateral. They tend to be sparse and do not normally exceed 1–2 mm in diameter. The renal microcysts in the image here reported are subtle, but consistent with lithium-induced chronic nephropathy. An MRI of the kidneys provides noninvasive evidence that strengthens the diagnosis of lithium-induced nephropathy.

A Higher Foci Density of Interstitial Fibrosis and Tubular Atrophy Predicts Progressive Chronic Kidney Disease after a Radical Nephrectomy for Tumor

2021 ◽  
pp. ASN.2021020267
Author(s):  
Luisa Ricaurte ◽  
Aleksandar Denic ◽  
Aidan Mullan ◽  
Ramya Narasimhan ◽  
Marija Bogojevic ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Radical Nephrectomy ◽  
Clinical Characteristics ◽  
Interstitial Fibrosis ◽  
Tubulointerstitial Injury ◽  
Tubular Atrophy ◽  
Cox Models ◽  
Lower Egfr ◽  
Global Glomerulosclerosis

Background Chronic tubulointerstitial injury on kidney biopsy is usually quantified by the percentage of cortex with interstitial fibrosis/tubular atrophy (IF/TA). Whether other patterns of IF/TA or inflammation in the tubulointerstitium have prognostic importance beyond percentage IF/TA is unclear. Methods We obtained, stained, and digitally scanned full cortical thickness wedge sections of renal parenchyma from patients who underwent a radical nephrectomy for tumor in 2000 to 2015 and morphometrically analyzed the tubulointerstitium of the cortex for percentage IF/TA, IF/TA density (foci per mm2 cortex), percentage subcapsular IF/TA, striped IF/TA, percentage inflammation (both within and outside IF/TA regions), and percentage subcapsular inflammation. Patients were followed with visits every 6-12 months. Progressive chronic kidney disease (CKD) was defined as dialysis, kidney transplantation, or 40% decline from the postnephrectomy estimated glomerular filtration rate (eGFR). Cox models assessed risk of CKD or noncancer mortality with morphometric measures of tubulointerstitial injury after adjustment for percentage IF/TA and clinical characteristics. Results Among 936 patients (mean age, 64 years; postnephrectomy baseline eGFR, 48 ml/min per 1.73m2), 117 progressive CKD events and 183 noncancer deaths occurred over a median 6.4 years. Higher IF/TA density predicted both progressive CKD and noncancer mortality after adjustment for percentage IF/TA and predicted progressive CKD after further adjustment for clinical characteristics. Independent of percentage IF/TA, age, and sex, higher IF/TA density correlated with lower eGFR, smaller nonsclerosed glomeruli, more global glomerulosclerosis, and smaller total cortical volume. Conclusions Higher density of IF/TA foci (a more scattered pattern with more and smaller foci) predicts higher risk of progressive CKD after radical nephrectomy compared with the same percentage of IF/TA but with fewer and larger foci.

scholarly journals Impaired Nicotinamide Adenine Dinucleotide Biosynthesis in the Kidney of Chronic Kidney Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Xinhui Liu ◽  
Denggui Luo ◽  
Shiying Huang ◽  
Siqi Liu ◽  
Bing Zhang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Nicotinamide Adenine Dinucleotide ◽  
De Novo ◽  
Periodic Acid ◽  
Public Health Problem ◽  
Nicotinamide Adenine ◽  
High Morbidity ◽  
Rat Models ◽  
Key Enzymes

Chronic kidney disease (CKD) is a global public health problem with high morbidity and mortality. Decreased nicotinamide adenine dinucleotide (NAD+) levels were found to be associated with aging, cancer, and neurodegenerative and metabolic disorders. However, the alteration of renal NAD+ levels and biosynthesis pathways in CKD is less known. In the present study, we aimed to evaluate renal NAD+ levels and tested the expression of key enzymes in three NAD+ biosynthesis pathways in two different types of CKD rat model. CKD rat models were established by 5/6 nephrectomy (5/6 Nx) and feeding with adenine-containing feed, respectively. Renal function was assessed by serum creatinine (Scr) and blood urea nitrogen (BUN). Renal pathology was evaluated by periodic acid-Schiff (PAS) and Masson’s trichrome staining. The expression of key enzymes in three NAD+ biosynthesis pathways was determined and quantified by Western blot analysis. The results showed CKD rat models were successfully established as evidenced by increased Scr and BUN levels, upregulation of neutrophil gelatinase-associated lipocalin (NGAL), glomerular hypertrophy, and renal fibrosis. Renal NAD+ and NADH content were both declined in two CKD rat models, and NAD+ levels were negatively correlated with Scr and BUN levels in CKD rats. Three key enzymes involved in NAD+ biosynthesis were significantly downregulated in the kidney of both of the two CKD models. They were quinolinate phosphoribosyltransferase (QPRT) in the de novo pathway, nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), and NMNAT3 in the salvage pathway. Moreover, the expression of NAD+-consuming enzymes sirtuin 3 (SIRT3) and CD38 decreased significantly in CKD rats. In conclusion, NAD+ biosynthesis was significantly impaired in CKD, which may attribute to downregulation of QPRT and NMNAT 1/3.

scholarly journals Renoprotective Effects of ETA Receptor Antagonists Therapy in Experimental Non-Diabetic Chronic Kidney Disease: Is There Still Hope for the Future?

2018 ◽  
pp. S55-S67 ◽  
Author(s):  
I. VANĚČKOVÁ ◽  
S. HOJNÁ ◽  
M. KADLECOVÁ ◽  
Z. VERNEROVÁ ◽  
L. KOPKAN ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Cell Injury ◽  
Interstitial Fibrosis ◽  
Experimental Studies ◽  
Tubular Atrophy ◽  
Eta Receptor ◽  
Life Threatening ◽  
Stage Renal Disease ◽  
End Stage

Chronic kidney disease (CKD) is a life-threatening disease arising as a frequent complication of diabetes, obesity and hypertension. Since it is typically undetected for long periods, it often progresses to end-stage renal disease. CKD is characterized by the development of progressive glomerulosclerosis, interstitial fibrosis and tubular atrophy along with a decreased glomerular filtration rate. This is associated with podocyte injury and a progressive rise in proteinuria. As endothelin-1 (ET-1) through the activation of endothelin receptor type A (ETA) promotes renal cell injury, inflammation, and fibrosis which finally lead to proteinuria, it is not surprising that ETA receptors antagonists have been proven to have beneficial renoprotective effects in both experimental and clinical studies in diabetic and non-diabetic CKD. Unfortunately, fluid retention encountered in large clinical trials in diabetic CKD led to the termination of these studies. Therefore, several advances, including the synthesis of new antagonists with enhanced pharmacological activity, the use of lower doses of ET antagonists, the addition of diuretics, plus simply searching for distinct pathological states to be treated, are promising targets for future experimental studies. In support of these approaches, our group demonstrated in adult subtotally nephrectomized Ren-2 transgenic rats that the addition of a diuretic on top of renin-angiotensin and ETA blockade led to a further decrease of proteinuria. This effect was independent of blood pressure which was normalized in all treated groups. Recent data in non-diabetic CKD, therefore, indicate a new potential for ETA antagonists, at least under certain pathological conditions.

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