Renal Metabolism Research Articles

Obstructive nephropathy and molecular pathophysiology of renal interstitial fibrosis.

The kidneys play a key role in maintaining total body homeostasis. The complexity of this task is reflected in the unique architecture of the organ. Ureteral obstruction greatly affects renal physiology by altering hemodynamics, changing glomerular filtration and renal metabolism, and inducing architectural malformations of the kidney parenchyma, most importantly renal fibrosis. Persisting pathological changes lead to chronic kidney disease, which currently affects ∼10% of the global population and is one of the major causes of death worldwide. Studies on the consequences of ureteral obstruction date back to the 1800s. Even today, experimental unilateral ureteral obstruction (UUO) remains the standard model for tubulointerstitial fibrosis. However, the model has certain limitations when it comes to studying tubular injury and repair, as well as a limited potential for human translation. Nevertheless, ureteral obstruction has provided the scientific community with a wealth of knowledge on renal (patho)physiology. With the introduction of advanced omics techniques, the classical UUO model has remained relevant to this day and has been instrumental in understanding renal fibrosis at the molecular, genomic, and cellular levels. This review details key concepts and recent advances in the understanding of obstructive nephropathy, highlighting the pathophysiological hallmarks responsible for the functional and architectural changes induced by ureteral obstruction, with a special emphasis on renal fibrosis.

Fucoidan Attenuated Kidney and Bone Damage Caused by CKD-MBD in Mice by Upregulating Klotho

Background Fucoidan is a phosphorylated polysaccharide extracted from seaweed that has a renal protective effect. However, whether Fucoidan can be used to prevent chronic kidney disease with mineral and bone disorders (CKD-MBD) is still a mystery and thus becomes the target of this research. Materials and Methods CKD-MBD mouse models were constructed, and the effects of Fucoidan and Klotho on CKD-MBD were determined through treatment of Fucoidan (100 mg/kg or 200 mg/kg) by gavage or tail vein injection of Klotho specific to small interfering RNA (siKlotho). The biochemical indicators related to renal function and bone metabolism in serum were detected by an automatic biochemical analyzer or enzyme-linked immunosorbent assay. Bone density was measured by X-ray. The effect of Fucoidan or siKlotho on kidney damage was tested by hematoxylin and eosin (H&E) staining or Elastica Masson-Goldner (EMG) staining. The expressions of Klotho, Runt-related transcription factor 2 (Runx2), and α-smooth muscle actin (α-SMA) in kidney tissue after Fucoidan treatment and/or siKlotho injection were quantified by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), immunohistochemistry, or Western blot. Results Fucoidan treatment inhibited the levels of blood urea nitrogen (BUN), creatinine, alkaline phosphatase (ALP), phosphorus, intact parathyroid hormone (iPTH), and fibroblast growth factor 23 (FGF23), while promoting 1,25 (OH)2D3 levels in serum. Fucoidan also increased bone density in mice, alleviated kidney damage and fibrosis of kidney tissue, promoted the expression of Klotho and Runx2, and inhibited the expression of α-SMA in kidney tissue. However, the above-mentioned therapeutic effects of Fucoidan were all reversed by siKlotho. Conclusion Fucoidan prevents CKD-MBD by up-regulating Klotho levels.

Isotopomer analyses with the tricarboxylic acid cycle intermediates and exchanging metabolites from the rat kidney.

Renal metabolism is essential for kidney functions and energy homeostasis in the body. The TCA cycle is the hub of metabolism, but the metabolic activities of the cycle in the kidney have rarely been investigated. This study is to assess metabolic processes at the level of the TCA cycle in the kidney based on isotopomer distributions in multiple metabolites. Isolated rat kidneys were perfused with media containing common substrates including lactate and alanine for an hour. One group of kidneys received [U-13 C3 ]lactate instead of natural abundance lactate while the other group received [U-13 C3 ]alanine instead of natural abundance alanine. Perfused kidneys and effluent were prepared for analysis using NMR spectroscopy. 13 C-labeling patterns in glutamate, fumarate, aspartate and succinate from the kidney extracts showed that pyruvate carboxylase and oxidative metabolism through the TCA cycle were comparably very active, but pyruvate cycling and pyruvate dehydrogenase were relatively less active. Isotopomer analyses with fumarate and malate from effluent, however, indicated that pyruvate carboxylase was much more active than the TCA cycle and other metabolic processes. The reverse equilibrium of oxaloacetate with four-carbon intermediates of the cycle was nearly complete (92%), based on the ratio of [2,3,4-13 C3 ]/[1,2,3-13 C3 ] in aspartate or malate. 13 C enrichment in glucose with 13 C-lactate supply was higher than that with 13 C-alanine. Isotopomer analyses with multiple metabolites (i.e., glutamate, fumarate, aspartate, succinate and malate) allowed us to assess relative metabolic processes in the TCA cycle in the kidney supplied with [U-13 C3 ]lactate. Data from the analytes were generally consistent, indicating highly active pyruvate carboxylase and oxidative metabolism through the TCA cycle. Different 13 C-labeling patterns in analytes from the kidney extracts versus effluent suggested metabolic compartmentalization.

Renal ectopic lipid deposition in rats with early-stage diabetic nephropathy evaluated by the MR mDixon-Quant technique: association with the expression of SREBP-1 and PPARα in renal tissue.

Renal ectopic lipid deposition (ELD) plays a significant role in the development of diabetic nephropathy (DN). This study aimed to use the magnetic resonance (MR) mDixon-Quant technique to evaluate renal ELD and its association with the expression of sterol regulatory element binding protein 1 (SREBP-1) and peroxisome proliferator-activated receptor alpha (PPARα) in renal tissue. Seventy male Sprague-Dawley (SD) rats were randomly divided into experimental (n=50) and control groups (n=20). A high-fat diet combined with low-dose streptozotocin (STZ) was administered to the experimental group to establish a type 2 diabetes mellitus (T2DM) model. The rats received renal mDixon-Quant scans and blood lipid and histopathological examinations in batches after the T2DM model was established. According to the histopathological findings, the included rats were stratified into control and early DN groups. Renal fat fraction (FF), blood lipid level, the ratio of the integrated optical density of intracellular lipid droplets and the total area of all the cells (IOD/TAC), and the expression of SREBP-1 and PPARɑ in renal tissue were analyzed. Compared to the controls, renal FF, IOD/TAC, the expression of SREBP-1 in renal tissue, and serum total cholesterol (TC), triglyceride (TG) and low-density lipoprotein (LDL) levels were higher in the early DN group, while the expression of PPARɑ in renal tissue and the high-density lipoprotein (HDL) level were lower (all P values <0.001). Renal FF gradually increased with the progression of disease [r=0.810 (95% CI: 0.675-0.928), P<0.001]. Positive correlations between renal FF and each of the following: TC, TG, LDL, IOD/TAC, and the expression of SREBP-1 [r=0.479 (95% CI: 0.353-0.640, P=0.012), 0.576 (95% CI: 0.283-0.842, P=0.002), 0.441 (95% CI: 0.305-0.606, P=0.021), 0.911 (95% CI: 0.809-0.964, P<0.001) and 0.800 (95% CI: 0.640-0.910, P<0.001), respectively] and negative correlations between renal FF and each of the following: HDL and the expression of PPARɑ [r=-0.611 (95% CI: -0.809 to -0.469, P=0.001) and -0.748 (95% CI: -0.886 to -0.585, P<0.001), respectively] were found. Renal lipid deposition evaluated by the MR mDixon-Quant technique is associated with the blood lipid level, histological fat quantification, and the expression of SREBP-1 and PPARɑ in renal tissue. The renal FF value might serve as a biomarker for better understanding of renal lipid metabolism in early-stage DN.

The antioxidant l-Ergothioneine prevents cystine lithiasis in the Slc7a9−/− mouse model of cystinuria

The high recurrence rate of cystine lithiasis observed in cystinuria patients highlights the need for new therapeutic options to address this chronic disease. There is growing evidence of an antioxidant defect in cystinuria, which has led to test antioxidant molecules as new therapeutic approaches. In this study, the antioxidant l-Ergothioneine was evaluated, at two different doses, as a preventive and long-term treatment for cystinuria in the Slc7a9−/− mouse model. l-Ergothioneine treatments decreased the rate of stone formation by more than 60% and delayed its onset in those mice that still developed calculi. Although there were no differences in metabolic parameters or urinary cystine concentration between control and treated mice, cystine solubility was increased by 50% in the urines of treated mice. We also demonstrate that l-Ergothioneine needs to be internalized by its transporter OCTN1 (Slc22a4) to be effective, as when administrated to the double mutant Slc7a9−/−Slc22a4−/− mouse model, no effect on the lithiasis phenotype was observed. In kidneys, we detected a decrease in GSH levels and an impairment of maximal mitochondrial respiratory capacity in cystinuric mice that l-Ergothioneine treatment was able to restore. Thus, l-Ergothioneine administration prevented cystine lithiasis in the Slc7a9−/− mouse model by increasing urinary cystine solubility and recovered renal GSH metabolism and mitochondrial function. These results support the need for clinical trials to test l-Ergothioneine as a new treatment for cystinuria.

8-LB: Adipocyte-Derived ANGPTL2 Regulates Abnormal Lipid Metabolism and Inflammation through PirB in Diabetic Kidney Disease

Diabetic kidney disease (DKD) is a disorder of glycolipid metabolism caused by diabetes mellitus, which leads to hemodynamic and inflammatory processes. The aim of this study is to investigate the mechanism of adipocyte-derived angiopoietin-like protein 2 (ANGPTL2) in promoting the progression of DKD. Patients with DKD were included, and plasma ANGPTL2 was detected by ELISA. Type 2 diabetic mouse model induced by HFD and STZ, systemic Angptl2 knockout mouse model and adipose-specific AAV-Angptl2 were constructed. HKC cells stimulated with high glucose and PA in vitro. ELISA was used to measure the levels of IL-6, IL-1β, TNF-α and ANGPTL2 in plasma. RT-qPCR and Western blot were used to detect PirB, lipid metabolism indicators and inflammation, and the proteomics of kidney was performed. HE, oil red O staining and inflammatory factor staining were used to evaluate the degree of renal lipid metabolism and inflammation. The plasma level of ANGPTL2 in DKD patients is significantly higher than that in normal controls. Compared with the normal mice, the DKD mice had increased lipid accumulation and severe inflammation in kidney tissues, with increased PirB, Cybb and pro-inflammatory factors, and decreased CD36 and FATP2 in kidney. Similarly, overexpression of adipose-derived ANGPTL2 in mice caused the same abnormal lipid metabolism and increased inflammation levels, while Angptl2 ko mice significantly improved lipid deposition and inflammation levels and fatty acid transport. Knockdown of ANGPTL2 in HKC cells also inhibited the reduction of CD36 and FATP2, the increase of its receptor PirB, and the increase of Cybb /Nox2-mediated inflammatory cytokines induced by high glucose and high lipid in HKC cells. Adipose-derived ANGPTL2 may play an important role in lipid metabolism and Cybb/ NOX2-regulated inflammatory through its receptor in DKD, suggesting that ANGPTL2 may serve as a potential treatment for preventing the progression of DKD. Disclosure R. Yin: None. L. Yang: None. D. Zhao: None. Funding National Natural Science Foundation of China (82170454)

11-OR: Fetal Renal Hypoxia Response to Maternal Overnutrition

Currently, 50% of women of reproductive age are obese, and one in seven live births is affected by hyperglycemia in mothers with gestational diabetes. To examine the impact of intrauterine overnutrition on the kidneys of the offspring, we generated a novel mouse model by feeding female C57BL6J mice with either control diet (CD) or high-fat diet (HFD, 60% Lipid) during gestation and feeding the male offspring with CD after weaning, allocated to two groups of male offspring, CD and HFD. CD and HFD had similar body weights, blood pressure and urinary albumin levels, but lower serum creatinine levels in HFD (CD; n=17, HFD; n=11, p&amp;lt;0.001), which might be due to renal hyperfiltration. Histologically, HFD presented renal tubular vacuolation at 4 weeks of age and glomerulosclerosis and intrarenal arteriosclerotic lesions at 15 weeks of age. Moreover, perirenal beige fat phenotype was lost in HFD at 4 week of age, presenting white adipose cells unlike the small adipose cells in CD, suggesting that maternal overnutrition induced systemic metabolic abnormality in offspring. Synchrotron phase-contrast micro-CT showed that HFD at 14.5 dpc showed asignificant increase in total kidney volume (CD; n=4, HFD; n=6, p&amp;lt;0.001). On the contrary, no significant difference in renal artery diameter was observed (p=0.52). Blood flow is determined by the supplying vascular diameter due to Murrays’ minimum energy hypothesis. Therefore, we studied the ratio of blood flow as the 3rd power of the diameter of fetal renal artery per renal volume, indicating no significant difference between CD and HFD (p=0.42). Despite of preserved blood supply, the protein expression of HIF-1α, the key hypoxic transcription factor, was higher in HFD than that in CD, suggesting increased oxygen demand due to maternal overnutrition-induced renal metabolism. Maternal overnutrition induces supply-demand mismatch leading to renal hypoxia in the fetus, which persists into adulthood in the offspring, which might promote susceptibility to diabetic nephropathy. Disclosure T.Takiyama: None. Y.Takiyama: None. R.Bessho: None. H.Kitsunai: None. Y.Takiyama: Research Support; Boehringer Ingelheim Japan, Inc., Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Abbott Japan Co., Ltd., Roche Diabetes Care, MSD Life Science Foundation, Japan Society for the Promotion of Science, Teijin Pharma Limited, Kyowa Kirin Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly Japan K.K.

#4542 L-ARGININE-NITRIC OXIDE MOLECULAR PATHWAY IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

Abstract Background and Aims Autosomal Dominant Polycystic Kidney Disease (ADPKD) is an inherited, complex disease, cystogenesis and phenotypic changes in this disorder being not yet fully understood. Recently, arginine, important for renal cells metabolism, was proved to play an important role in ADPKD physiopathology (1). The inability of cells to recycle or synthesize intracellular arginine through the urea cycle is defined as arginine auxotrophy. Arginine auxotrophy in ADPKD induces cell hyperproliferation, and cysts formation (2). We aimed to explore L-Arginine (Arg) - Nitric Oxide (NO) molecular pathway in ADPKD, a multisystemic, arginine auxotrophe disease. Method We developed a prospective, case control study, in Carol Davila Clinical Hospital of Nephrology, Bucharest, Romania. The study included a group of 62 subjects with ADPKD (mean age -54.3years old, men:women 34:28, with 1A and 1B Mayo ADPKD risk classes) and a group of 37 healthy subjects, similar as sex, mean age. ADPKD diagnosis was based on familial history, clinical exam and CT or MRI scan. We excluded from the study subjects that presented cysts in other organs except the kidney, with eGFR&amp;lt;60mL/min/1.73mp, with history of hematuria, cysts infection, urinary tract infection, renal lithiasis, with unstable blood pressure and hypertensive treatment for less than 6 months; metabolic disorders (carbamoyl phosphate synthase 1 and N-acetyl glutamate synthase deficiencies, lack of ornithine transcarbamilase, hyperargininemia, phenylketonuria). Laboratory tests: serum level of arginine, enzymatic activity of arginase 2 (ARG-2) and nitric oxide inducible synthase (NOS-2), serum levels of stable metabolites of nitric oxide (nitrate, direct nitrite, total nitrite), endogenous inhibitors of nitric oxide synthesis (Asymmetric Dimethylarginine -ADMA, Symmetric Dimethylarginine SDMA). Results In ADPKD patients, the serum levels of arginine and of the stable metabolites of nitric oxide had statistically significant lower levels compared with control group (Table 1). The levels of the principal enzymes that metabolizes arginine – arginase 2 and nitric oxide inducible synthase, respectively the endogenous inhibitors of nitric oxide synthesis were statistically significant higher in ADPKD group when compared with control group (Table 1). The ARG2/Arg, NOS2/Arg, Nitrite/Arg, Nitrate/Arg, ADMA/Arg and SDMA/Arg ratios were statistically significant overexpressed in ADPKD group when compared with control group. Conclusion ADPKD is a metabolic kidney disease, auxotrophic for arginine. The metabolic ADPKD phenotype of renal cells with low risk of progression (1A and 1B Mayo) is defined by the alteration of L-Arginine-NO molecular pathway, the significant reduction of systemic arginine, moderately increased enzymatic activities of ARG2 and NOS2, the reduction of the synthesis and bioactivity of NO. Exploring arginine reprogramming and related molecular L-Arg-NO pathways disturbances could offer more information about ADPKD physiopathology.

#6823 THE NUTRITIONAL AND NEPHROLOGICAL IMPACT OF A LOW-NORMAL PROTEIN HIGH CALORIE DIET ON THE ONCOLOGICAL SOLITARY KIDNEY: TIME FOR A NEW PERSPECTIVE?

Abstract Background and Aims Nutritional therapy (NT) based on controlled protein intake represents a cornerstone in the management of chronic kidney disease (CKD). However the international guidelines do not precisely define an adequate protein intake for nephrological patients affected by cancer, the onco-nephrological ones. Among them, there is a precise asset where a personalized nutritional strategy can make the difference; the oncological patients who remain with a solitary kidney due to a radical nephrectomy for renal cancer. In fact, the acute decrease of GFR due to the loss of an entire kidney leads these patients to develop a mild to severe stage of CKD and this pathological condition should require a nephrological diet with protein restriction based upon GFR levels. However, in routinary clinical practice this cohort of patients tend to be followed by oncologists who apply a completely opposite nutritional approach with a high protein diet for the presence of cancer in order to avoid catabolism, malnutrition and sarcopenia. The aim of our study was to investigate whether a Low-Normal Protein High Calorie (LNPHC) diet in a nephrologist-nutritionist combined approach (NNCA) and aimed at CKD patients can also be effective in improving the nutritional status in solitary cancer kidney patients without compromising the renal function and metabolism. Method A consecutive cohort of 44 pts was enrolled in the Urological Department at San Raffaele Scientific Institute between 2018-2021. Inclusion criteria were: Age (&amp;gt;18 years old), eGFR (&amp;lt;60 ml/min/1.73), Malnutritional Screening Tool (MST&amp;lt;2), Solitary kidney for radical nephrectomy for renal cancer, informed consent (signed). Each patient underwent an initial nephrological and nutritional evaluation and was subsequently subjected to a conventional CKD LNPHC diet integrated with aproteic foods (0,7-1 g/Kg/die: calories: 30-35 kcal per kg body weight/die) for a period of 6 months (+/- 2 moths). The diet was based on the estimated Glomerular Filtration Rate (CKD-EPI 2021 Creatinin formula), comorbidities and nutritional status. MST, Body Mass Index (BMI), Phase Angle (PA), Fat Mass percentage (FM%), Fat-Free Mass Index (FFMI), body cell mass index (BCMI), extracellular/intracellular water ratio (ECW/ICW), waist/hip circumference ratio (WHC), lab test exams and clinical variables were examined at baseline and after 6 months. Statistical analysis: Kruskal-Wallis rank sum test; Data analysis: R programming language and RStudio integrated development environment. Results Descriptive analysis is showed in Table 1. Our results clearly highlighted that LNPHC was able to generate a significant improvement in all the investigated nutritional parameters (Table 2 and 3) avoiding malnutrition or catabolism. Moreover, regarding the nephrological asset, LNPHC was responsible for a significant decrease of urea, the most important parameter influencing general status. The non-significant increase of serum creatinine and therefore decrease of eGFR was related to the augmented muscle mass (Table 4). Conclusion LNPHC represents a new important therapeutic strategy to apply in the onco-nephrological patients with solitary kidney due to renal cancer.

Huangqi-Danshen decoction reshapes renal glucose metabolism profiles that delays chronic kidney disease progression

Huangqi-Danshen decoction (HDD), a Chinese herbal preparation, is effective in clinical treatment of chronic kidney disease (CKD). However, the underlying mechanism remains to be clarified. In this study, we aimed to investigate the role of HDD in the regulation of renal glucose metabolism in a CKD mouse model. The 0.2% adenine-induced CKD mouse model was administered HDD extract at a dose of 6.8 g/kg/day for 4 weeks. Detection of renal glucose metabolites was performed by ultra-performance liquid chromatography-tandem mass spectrometry. The expression of renal fibrosis and glucose metabolism-related proteins was tested by Western blotting, immunohistochemistry, and immunofluorescence. The results showed that HDD treatment could significantly reduce serum creatinine (0.36 ± 0.10 mg/dL vs. 0.51 ± 0.07 mg/dL, P < 0.05) and blood urea nitrogen (40.02 ± 3.73 mg/dL vs. 62.91 ± 10 mg/dL, P < 0.001) levels, and improve renal pathological injury and fibrosis. Aberrant glucose metabolism was found in the kidneys of CKD mice, manifested by enhanced glycolysis and pentose phosphate pathway, and tricarboxylic acid cycle inhibition, which could be partially restored by HDD treatment. Furthermore, HDD regulated the expression of hexokinase 2, phosphofructokinase, pyruvate kinase M2, pyruvate dehydrogenase E1, oxoglutarate dehydrogenase, and glucose-6-phosphate dehydrogenase in CKD mice. In conclusion, HDD protected against adenine-induced CKD, reshaped glucose metabolism profiles, and restored the expression of key enzymes of glucose metabolism in the kidneys of CKD mice. This study sheds light on targeting glucose metabolism for the treatment of CKD and screening small molecule compounds from herbal medicine to slow CKD progression.

Elevated angiopoietin-like protein 3 serum levels in diabetic nephropathy patients and its association with renal function and lipid profile

BackgroundType 2 diabetes mellitus (T2DM) is a highly prevalent disease that has life-threatening consequences like micro and macrovascular complication. Diabetic nephropathy (DN) is one of the common consequences of T2DM which is related to secretory factors like hepatokines. Angiopoietin-Like Protein 3 (ANGPTL3) is a hepatokine that is perturbated in cardiometabolic diseases and experimental studies showed its effect on renal functions and lipid metabolism. For the first time, ANGPTL3 was measured in patients with T2DM and DN in the present study.MethodsSerum levels of ANGPTL3, IL-6, and TNF-α were measured in 60 healthy control, 60 T2DM patients, and 61 DN patients.ResultsSerum levels of ANGPTL3 increased in T2DM (252.39 ± 66.01) and DN (284.59 ± 69.27) patients compared to controls (160.22 ± 48.96), and DN patients compared with T2DM patients. Urinary albumin excretion (UAE) was higher in the DN group compared to T2DM and control groups. Moreover, serum levels of IL-6 and TNF-α were elevated in both patient groups compared to controls. Moreover, ANGPTL3 represented a positive correlation with triglycerides, creatinine, and UAE in patients with both T2DM and DN groups and showed an inverse correlation with eGFR in patients with DN. Moreover, this hepatokine had a good potential to differentiate patients from controls, especially, DN patients.Conclusionsthese findings provide invivo evidence for the relation of ANGPTL3 with renal dysfunction and hypertriglyceridemia in patients with DN which is in line with experimental findings and suggested a potential role for this hepatokine in DN pathogenesis.

Renal Oxygen Demand and Nephron Function: Is Glucose a Friend or Foe?

The kidneys and heart work together to balance the body's circulation, and although their physiology is based on strict inter dependence, their performance fulfills different aims. While the heart can rapidly increase its own oxygen consumption to comply with the wide changes in metabolic demand linked to body function, the kidneys physiology are primarily designed to maintain a stable metabolic rate and have a limited capacity to cope with any steep increase in renal metabolism. In the kidneys, glomerular population filters a large amount of blood and the tubular system has been programmed to reabsorb 99% of filtrate by reabsorbing sodium together with other filtered substances, including all glucose molecules. Glucose reabsorption involves the sodium-glucose cotransporters SGLT2 and SGLT1 on the apical membrane in the proximal tubular section; it also enhances bicarbonate formation so as to preserve the acid-base balance. The complex work of reabsorption in the kidney is the main factor in renal oxygen consumption; analysis of the renal glucose transport in disease states provides a better understanding of the renal physiology changes that occur when clinical conditions alter the neurohormonal response leading to an increase in glomerular filtration pressure. In this circumstance, glomerular hyperfiltration occurs, imposing a higher metabolic demand on kidney physiology and causing progressive renal impairment. Albumin urination is the warning signal of renal engagement over exertion and most frequently heralds heart failure development, regardless of disease etiology. The review analyzes the mechanisms linked to renal oxygen consumption, focusing on sodium-glucose management.

The role of interleukin-6 in the pathogenesis of protein-energy malnutrition in patients treated with haemodialysis

BACKGROUND. Protein-energy malnutrition (PEM) often develops in patients receiving long-term treatment with programmed haemodialysis (HD). Its main causes are decreased intake of basic nutrients, increased losses, disorders inherent to the terminal renal failure itself (including chronic inflammation), as well as the influence of factors associated with the HD procedure. THE AIM: to clarify the role of interleukin-6 (IL-6 ) in the pathogenesis of BEN in patients treated with programmed haemodialysis. PATIENTS AND METHODS. We examined 645 patients receiving HD treatment, including 300 men and 345 women aged 56.8±12.8 years, the duration of renal replacement therapy was 8.4±5.3 years. Nutritional status was assessed according to International Society of Renal Nutrition and Metabolism (ISRNM) recommendations. Serum IL-6 levels were determined by a three-step "sandwich" version of a solid phase enzyme immunoassay using mono- and polyclonal antibodies to IL-6 using a commercial kit "Interleukin-6-IFA-BEST" from Vector-Best, Russia, under the manufacturer's instructions. The reference values for IL-6 are 0-7 pg/ml. RESULTS. The prevalence of BEN was 24.9 % (160 patients). Mean IL-6 concentration was 6.47±2.64 pg/ml in patients without evidence of BEN, and 23.20±10.40 pg/ml in patients with BEN, p&lt;0.001. Elevated IL-6 levels revealed statistically significantly lower levels of total protein, albumin, prealbumin, total cholesterol, transferrin and blood lymphocyte counts. Patients with elevated IL-6 levels were also characterized by statistically significantly lower values of body mass index, skeletal muscle mass index and skeletal muscle mass index. CONCLUSION. The results of this study suggest that the high prevalence of PEM in patients treated with HD is closely related to an imbalance of pro- and anti-inflammatory cytokines. An increase in the duration of renal replacement therapy is accompanied by an increase in serum IL-6 levels. Therefore, this cytokine can be considered as a therapeutic target for prevention and treatment of sarcopenia in dialysis patients.

Oxalate as a potent promoter of kidney stone formation.

Kidney stones are among the most prevalent urological diseases, with a high incidence and recurrence rate. Treating kidney stones has been greatly improved by the development of various minimally invasive techniques. Currently, stone treatment is relatively mature. However, most current treatment methods are limited to stones and cannot effectively reduce their incidence and recurrence. Therefore, preventing disease occurrence, development, and recurrence after treatment, has become an urgent issue. The etiology and pathogenesis of stone formation are key factors in resolving this issue. More than 80% of kidney stones are calcium oxalate stones. Several studies have studied the formation mechanism of stones from the metabolism of urinary calcium, but there are few studies on oxalate, which plays an equally important role in stone formation. Oxalate and calcium play equally important roles in calcium oxalate stones, whereas the metabolism and excretion disorders of oxalate play a crucial role in their occurrence. Therefore, starting from the relationship between renal calculi and oxalate metabolism, this work reviews the occurrence of renal calculi, oxalate absorption, metabolism, and excretion mechanisms, focusing on the key role of SLC26A6 in oxalate excretion and the regulatory mechanism of SLC26A6 in oxalate transport. This review provides some new clues for the mechanism of kidney stones from the perspective of oxalate to improve the understanding of the role of oxalate in the formation of kidney stones and to provide suggestions for reducing the incidence and recurrence rate of kidney stones.

Scribble scrambles parathyroid hormone receptor interactions to regulate phosphate and vitamin D homeostasis

G protein-coupled receptors, including PTHR, are pivotal for controlling metabolic processes ranging from serum phosphate and vitamin D levels to glucose uptake, and cytoplasmic interactors may modulate their signaling, trafficking, and function. We now show that direct interaction with Scribble, a cell polarity-regulating adaptor protein, modulates PTHR activity. Scribble is a crucial regulator for establishing and developing tissue architecture, and its dysregulation is involved in various disease conditions, including tumor expansion and viral infections. Scribble co-localizes with PTHR at basal and lateral surfaces in polarized cells. Using X-ray crystallography, we show that colocalization is mediated by engaging a short sequence motif at the PTHR C-terminus using Scribble PDZ1 and PDZ3 domain, with binding affinities of 31.7 and 13.4 μM, respectively. Since PTHR controls metabolic functions by actions on renal proximal tubules, we engineered mice to selectively knockout Scribble in proximal tubules. The loss of Scribble impacted serum phosphate and vitamin D levels and caused significant plasma phosphate elevation and increased aggregate vitamin D3 levels, whereas blood glucose levels remained unchanged. Collectively these results identify Scribble as a vital regulator of PTHR-mediated signaling and function. Our findings reveal an unexpected link between renal metabolism and cell polarity signaling.

Energy Metabolism Dysregulation in Chronic Kidney Disease.

Chronic kidney disease (CKD) is a significant contributor to morbidity and mortality. A better understanding of mechanisms underlying CKD progression is indispensable for developing effective therapies. Towards this goal, we addressed specific gaps in knowledge regarding tubular metabolism in the pathogenesis of CKD using the subtotal nephrectomy (STN) model in mice. Weight- and age-matched male 129X1/SvJ mice underwent sham or STN surgeries. We conducted serial glomerular filtration rate (GFR) and hemodynamic measurements up to 16 weeks after sham and STN surgery and established the 4-week timepoint for subsequent studies. For a comprehensive assessment of renal metabolism, we conducted transcriptomic analyses, which showed significant enrichment of pathways involved in fatty acid metabolism, gluconeogenesis, glycolysis, and mitochondrial metabolism in STN kidneys. Expression of rate-limiting fatty acid oxidation and glycolytic enzymes was increased in STN kidneys, and proximal tubules in STN kidneys exhibited increased functional glycolysis but decreased mitochondrial respiration, despite an increase in mitochondrial biogenesis. Assessment of the pyruvate dehydrogenase complex pathway showed significant suppression of pyruvate dehydrogenase suggesting decreased provision of acetyl CoA from pyruvate for the citric acid cycle to fuel mitochondrial respiration. In conclusion, metabolic pathways are significantly altered in response to kidney injury and may play an important role in the disease progression.

July Meeting Announcements

October 7-10, 2023, Academy of Nutrition and Dietetics, Food and Nutrition Conference and Expo (FNCE) 2023, Colorado Convention Center, Denver, CO. www.eatright.org/FNCE or call 800-877-1600 ext. 4862. October 14-16, 2023, American Nephrology Nurses Association (ANNA) Fall Meeting, Hilton Chicago, Chicago, IL. www.annanurse.org/events/2023-nephrology-nursing-practice-management-leadership-conference or call 888-600-2662. November 2-5, 2023, American Society of Nephrology (ASN) Kidney Week 2023, Pennsylvania Convention Center, Philadelphia, PA. www.asn-online.org/education or call 866-849-8868. April 13-16, 2024, International Society of Nephrology (ISN) World Congress of Nephrology 2024, Buenos Aires, Argentina. Visit www.theisn.org/wcn. April 14-17, 2024, American Nephrology Nurses Association (ANNA) 2024 Natl Symp Caribe Royale All Suite Hotel Convention Cent Orlando, FL. www.ananurse.org/events/2024-national-symposium or call 888-600-2662 May 14-18, 2024, National Kidney Foundation (NKF) Spring Clinical Meeting, Long Beach, CA. Visit www.kidney.org. or call 800-622-9010. May 23-26, 2024, 61st European Renal Association-European Dialysis and Transplantation Association (ERA-EDTA) Congress, Stockholmsmassan, Stockholm, Sweden, [email protected]. August 28-31, 2024, International Society on Renal Nutrition and Metabolism, 21st Congress of the International Society of Renal Nutrition and Metabolism, Hyderabad, India. www.icrnm2024.com. September 26-29, 2024, International Society for Peritoneal Dialysis, 40th Anniversary Congress, Dubai, UAE. www.ispd.org/dubai2024.

Cadmium induced time-dependent kidney injury in common carp via mitochondrial pathway: Impaired mitochondrial energy metabolism and mitochondrion-dependent apoptosis

Toxic effect of heavy metal cadmium (Cd) on fish kidneys had been reported. Mitochondrion is an important organelle for maintaining kidney function, while its role in Cd-induced kidney injury in common carp remained unclarified. In this experiment, we established a poisoning model of common carp with Cd exposure (0.26 mg/L) for 15, 30, and 45 days. Serum biochemistry determination, histological observation, TUNEL assay, qRT-PCR, Western blot, and integrated biomarker response (IBR) were applied to assess the nephrotoxicity of Cd to common carp. Our results displayed that Cd exposure increased the levels of serum biochemical indexes (UREA, CRE, and UA), indicating kidney injury. We further revealed via histological observation that Cd damaged structural integrity of kidneys, as evidenced by renal glomerulus and renal tubular injury, hallmark phenotypes of apoptosis, and mitochondrial damage, suggesting that mitochondria damage and apoptosis were involved in Cd-induced kidney injury. Moreover, Cd exposure decreased ATPase (Na+/K+-ATPase, Ca2+-ATPase, Mg2+-ATPase, and Ca2+Mg2+-ATPase) activities as well as PGC-1a and Mfn2 levels, while increased Drp1 and PINK1 levels as well as LC3-II/LC3-I ratio, which indicated that Cd-impaired renal energy metabolism was related to mitochondrial dysfunction. Additionally, we found that Cd induced oxidative stress (abnormal levels of SOD, CAT, GPX, MDA, and H2O2) in kidneys, which was involved in triggering mitochondrial dysfunction and further impairing mitochondrial energy metabolism. Moreover, the occurrence of mitochondria-dependent apoptosis was found after Cd-exposure in common carp kidneys, as indicated by enhanced levels of Bax, CytC, APAF1, Caspase-9, and Caspase-3, while declined level of Bcl-2. Subsequently, we confirmed a time-dependent nephrotoxicity of Cd to common carp via IBR assessment. In conclusion, Cd induced time-dependent nephrotoxicity in common carp via mitochondrial pathway. This mitochondria-oriented study shed light on underlying mechanisms of Cd-induced renal pathologies and provided a theoretical basis for evaluating Cd toxicity to aquatic organisms.

Reduced urine volume and changed renal sphingolipid metabolism in P2ry14-deficient mice.

The UDP-glucose receptor P2RY14, a rhodopsin-like G protein-coupled receptor (GPCR), was previously described as receptor expressed in A-intercalated cells of the mouse kidney. Additionally, we found P2RY14 is abundantly expressed in mouse renal collecting duct principal cells of the papilla and epithelial cells lining the renal papilla. To better understand its physiological function in kidney, we took advantage of a P2ry14 reporter and gene-deficient (KO) mouse strain. Morphometric studies showed that the receptor function contributes to kidney morphology. KO mice had a broader cortex relative to the total kidney area than wild-type (WT) mice. In contrast, the area of the outer stripe of the outer medulla was larger in WT compared to KO mice. Transcriptome comparison of the papilla region of WT and KO mice revealed differences in the gene expression of extracellular matrix proteins (e.g., decorin, fibulin-1, fibulin-7) and proteins involved in sphingolipid metabolism (e.g., small subunit b of the serine palmitoyltransferase) and other related GPCRs (e.g., GPR171). Using mass spectrometry, changes in the sphingolipid composition (e.g., chain length) were detected in the renal papilla of KO mice. At the functional level, we found that KO mice had a reduced urine volume but an unchanged glomerular filtration rate under normal chow and salt diets. Our study revealed P2ry14 as a functionally important GPCR in collecting duct principal cells and cells lining the renal papilla and the possible involvement of P2ry14 in nephroprotection by regulation of decorin.

3-tert-Butyl-4-hydroxyanisole perturbs renal lipid metabolism in vitro by targeting androgen receptor-regulated de novo lipogenesis

The widespread usage of 3-tert-butyl-4-hydroxyanisole (3-BHA) as an anthropogenic antioxidant has caused considerable environmental contamination and frequent detection in diverse human-derived samples. 3-BHA can promote adipogenesis and impair hepatic lipid metabolism, while its effects on renal lipid homeostasis remain to be uncertain. Herein, using the human kidney 2 (HK-2) cell experiments, 3-BHA was found to cause a significant reduction in lipid accumulation of the HK-2 cells in both exposure concentration- and duration-dependent manners. Exposure to 3-BHA lowered the transcriptional expressions of sterol regulatory element-binding protein 1 (SREBP1) and acetyl-CoA carboxylase (ACC), as well as ACC activity, indicating the inhibition in the process of de novo lipogenesis in HK-2 cells. On this basis, the mechanism study suggested that the reduced glucose absorption and accelerated glycolysis were concomitantly involved. The antagonism of 3-BHA on the transactivation of androgen receptor (AR) contributed to the lowered de novo lipogenesis and the consequent intracellular lipid reduction. The metabolomics data further confirmed the imbalance of lipid homeostasis and dysregulation of de novo lipogenesis. The new findings on the impaired renal lipid metabolism induced by 3-BHA warranted proper care about the usage of this chemical as a food additive.