Mitochondrial Dysfunction in Cardiorenal Syndrome 3: Renocardiac Effect of Vitamin C

Cardiorenal syndrome (CRS) is a pathological link between the kidneys and heart, in which an insult in a kidney or heart leads the other organ to incur damage. CRS is classified into five subtypes, and type 3 (CRS3) is characterized by acute kidney injury as a precursor to subsequent cardiovascular changes. Mitochondrial dysfunction and oxidative and nitrosative stress have been reported in the pathophysiology of CRS3. It is known that vitamin C, an antioxidant, has proven protective capacity for cardiac, renal, and vascular endothelial tissues. Therefore, the present study aimed to assess whether vitamin C provides protection to heart and the kidneys in an in vivo CRS3 model. The unilateral renal ischemia and reperfusion (IR) protocol was performed for 60 min in the left kidney of adult mice, with and without vitamin C treatment, immediately after IR or 15 days after IR. Kidneys and hearts were subsequently collected, and the following analyses were conducted: renal morphometric evaluation, serum urea and creatinine levels, high-resolution respirometry, amperometry technique for NO measurement, gene expression of mitochondrial dynamic markers, and NOS. The analyses showed that the left kidney weight was reduced, urea and creatinine levels were increased, mitochondrial oxygen consumption was reduced, NO levels were elevated, and Mfn2 expression was reduced after 15 days of IR compared to the sham group. Oxygen consumption and NO levels in the heart were also reduced. The treatment with vitamin C preserved the left kidney weight, restored renal function, reduced NO levels, decreased iNOS expression, elevated constitutive NOS isoforms, and improved oxygen consumption. In the heart, oxygen consumption and NO levels were improved after vitamin C treatment, whereas the three NOS isoforms were overexpressed. These data indicate that vitamin C provides protection to the kidneys and some beneficial effects to the heart after IR, indicating it may be a preventive approach against cardiorenal insults.

The Effects of Two Different Dietary Regimens During Exercise On Outcome of Experimental Acute Kidney Injury

Introduction: Acute kidney injury (AKI) is a syndrome characterized by rapid loss of excretory function of kidney. One of the molecules considered in the treatment of renal failure is the silent information regulator (SIRT1). In this study, the effect of two different diets during exercise on AKI was investigated. Materials and Methods: A number of rats were randomly divided into four groups; control without exercise, control with exercise, exercise + calorie restriction (CR), and exercise + time restriction (TR). Each group was divided into two subgroups of without AKI and with AKI (six rats in each group). Endurance exercise and diets were implemented before AKI. Serum urea and creatinine, urinary albumin, kidney malondialdehyde (MDA), total antioxidant capacity (TAC), transforming growth factor (TGF-β1), and SIRT1 levels, glomerular filtration rate (GFR) and relative kidney weight were measured before and 48 h after AKI induction.Results: After induction of kidney injury, serum urea and creatinine, urinary albumin, kidney MDA and TGF-β1 levels and relative kidney weight increased in rats with both previous exercise and no previous exercise (p <0.001), while GFR, and kidney TAC and SIRT1 levels decreased (p <0.001). These changes after AKI were less in the group with previous exercise than in the group that had no exercise (p <0.001). The TR diet during exercise caused a less increase in serum urea (p <0.001) and creatinine (p <0.05), and urinary albumin (p <0.01) levels after injury compared to the just exercise group. Also, both CR and TR diets during exercise caused less change in MDA (p <0.01, p <0.05, respectively) and TAC (p <0.001, p <0.05, respectively) levels compared to just exercise group. Conclusion: The results showed that exercise alone had no effect on preventing function impairment of kidney, oxidative stress, inflammation and also SIRT1 alteration following AKI in athletes, although these indexes were less among those with exercise than those without exercise. However, when the CR and TR diets were implemented during exercise, strong renoprotective effects appeared, and the protective effect of TR diet was greater.

Evaluation of Renoprotective Effects of Our Locally Grown Green Coffee Beans against Cisplatin-Induced Nephrotoxicity in Swiss Albino Mice

Introduction. Nephrotoxicity is the most common and severe side effect of cisplatin. Cisplatin causes nephrotoxicity through free radical production and debilitating cellular antioxidant capacity. Coffee is a commonly consumed drink and its ingredients have antioxidant roles that could bring benefits to patients affected by nephrotoxicity. Thus, the present study aimed to investigate the renoprotective effects of our locally grown green coffee beans against cisplatin-induced nephrotoxicity in Swiss albino mice. Methods. The posttest only control group design was employed on a total of thirty male Swiss albino mice. The mice were divided into five groups: group I (normal control group) received distilled water; group II (negative control group) received distilled water; and groups III–V (treatment groups) received 100, 200, and 300 mg/kg BW/day of green coffee bean extract for 14 days, respectively. Nephrotoxicity was induced in groups II–V by a single intraperitoneal injection of cisplatin (7.5 mg/kg). All mice were sacrificed after 14 days and blood was drawn to evaluate kidney function tests (serum creatinine and serum blood urea nitrogen). Besides, body weight, relative kidney weight, and kidney histopathology were investigated. Result. Our results showed that treatment of cisplatin alone (group II mice) significantly increased serum creatinine, serum blood urea nitrogen, relative kidney weight, and pathological damage to the kidney with a decrease in final body weight. However, low-dose green coffee beans (group III), medium-dose green coffee beans (group IV), and high-dose green coffee beans (group V) mice showed a significant dose-dependent decrease in serum creatinine, serum blood urea nitrogen, and relative kidney weight. Furthermore, the dose-dependent treatment with green coffee bean extract prevented the decrease in body weight gain and pathological damage to the kidney in mice. Conclusion. Our locally grown green coffee beans brought a dose-dependent ameliorative effect and a promising preventive approach against cisplatin-induced kidney damage in mice.

A Case Report of Autopsy: Large Mass of Pulmonary Metastatic Calcification in a Patient with End-Stage Renal Disease

Introduction/Objective Metastatic calcifications are reported in patients with end-stage renal disease (ESRD) in radiology literature but there are no pathologic reports regarding this clinical scenario in autopsy. Methods/Case Report We report the case of a 27-year-old African American man with nephrotoxic injury secondary to gentamicin treatment at a young age leading to ESRD requiring dialysis who then later developed congestive heart disease and arrhythmia. Prior to the patient’s last hospitalization, he had normal breath sounds with no signs of respiratory distress, rales, or wheezing. Imaging of the chest showed a patchy density in the right lung and a large parenchymal calcification. During autopsy, the patient was found to have bilateral markedly small and atrophic kidneys (left kidney weight: 27.5 g, size: 5.7 x 4.4 x 3.0 cm and right kidney weight: 30.6 g, size: 5.9 x 4.4 x 3.1 cm). Microscopically, the kidneys showed diffuse global glomerulosclerosis, atrophy of cortex, severe interstitial fibrosis, and tubular atrophy with thickened arteries as well as many foci of calcifications. A large mass measuring 3.5 x 2.4 x 1.9 cm was identified in the right middle lobe of the lung. Sections of the mass revealed large calcifications which were confirmed microscopically. In addition, concentric heart hypertrophy was identified with heart weight of 925 g and left ventricle measuring up to 2.2 cm. Calcifications (ranging from 0.2 – 0.5 mm) were also identified on the left atrial wall as well as a 1.2 x 0.8 x 0.6 cm mitral valve nodule along with additional microcalcifications within the myocardium. Results (if a Case Study enter NA) NA Conclusion In conclusion, our autopsy case supports previous radiologic reports that metastatic calcification can be dramatically present in the lung in patients with ESRD.

Abstract P247: Elastin Insufficiency Impairs Renal Hemodynamics And Accelerates Aging-associated Structural And Functional Remodeling Of Preglomerular Arterioles

Elastin degradation and fragmentation are hallmarks of arterial stiffness and renal dysfunction associated with aging. However, it is unclear whether elastin insufficiency contributes to the changes in the structure and function of the resistance vasculature of the kidney during aging. Here we determined how increased vascular stiffness due to elastin insufficiency alters renal hemodynamics and mechanical properties of preglomerular arterioles. We assessed renal hemodynamics under anesthesia in 14-16-month-old female wild type (WT) and elastin heterozygous ( Eln +/- ) mice. Renal autoregulation was assessed by a stepwise increase in renal perfusion pressure (RPP) by simultaneously occluding the superior mesenteric and celiac arteries. Myogenic constriction and arterial stiffness were assessed by pressure myography of isolated renal interlobar arteries. Baseline renal vascular resistance (RVR) was elevated in Eln +/- mice (13.8 ± 2.9 vs 11.2 ± 1.4 mmHg/μL/min/g left kidney weight), while systolic blood pressure (SBP; 75.1 ± 7.4 vs 91 ± 4.2mmHg), renal blood flow (RBF; 6.3 ± 1.2 vs 7.4 ± 1.7 μL/min/g left kidney weight), renal plasma flow (RPF; 3.4 ± 0.8 vs 5 ± 1.2 mL/min/g/ left kidney weight) and urine flow rate, all trended lower in Eln +/- mice compared to WT mice. Glomerular filtration rate (GFR) and filtration fraction (FF) were similar between the two groups. A stepwise increase in RPP caused a slower decline and rise in RBF and RVR, respectively, in Eln +/- relative to WT mice. The maximal changes in RBF (5 ± 1.1 vs 4.7 ± 0.8 μL/min/g left kidney weight), RVR (17.6 ± 7.3 vs 22.5 ± 2.1 mmHg/μL/min/g left kidney weight), urine flow rate,GFR, and FF were less robust in Eln +/- mice. RPF decreased in WT mice in response to raising RPP, whereas it remained unchanged in Eln +/- mice. Myogenic response and increases in elastic modulus and wall tension following stepwise changes in intraluminal pressure were all augmented in interlobar arteries from Eln +/- relative to WT mice. However, there was no difference in kidney weight/tibia length ratio between the two genotypes. We conclude that elastin insufficiency impairs renal hemodynamics by exacerbating age associated increase in vascular stiffness.

Differential Effects of Green Tea Powders on the Protection of Brown Tsaiya and Kaiya Ducklings against Trichothecene T-2 Toxin Toxicity

A 3-week feeding trial in a 3 × 2 × 2 factorial design was conducted with three concentrations (0, 0.5, and 5 mg/kg) of T-2 toxin (T-2) and two levels (0% and 0.5%) of green tea powder (GTP) supplements used in the diets of female brown Tsaiya ducklings (BTDs) and Kaiya ducklings (KDs), respectively. Breed had a significant effect on the growth performances and the relative weights of organs and carcass. In general, the growth performances of KDs were better than BTDs. The relative weights of organs and carcass of BTDs were typically heavier than those of KDs; however, the breast of KDs was heavier than those of BTDs. Both ducklings received 5 mg/kg of T-2 blended in the diet showed lower feed intake and body weight gain (BWG) in the second and the third week. The diet containing 5 mg/kg of T-2 and 0.5% GTP improved the BWG compared to those fed the diet supplemented with 5 mg/kg of T-2 without GTP in BTDs. Ducklings fed the diet containing 5 mg/kg of T-2 induced hypocalcemia and hypomagnesemia, as well as decreased concentrations of creatine phosphokinase and alkaline phosphatase. The concentrations of blood urea nitrogen (BUN) and glutamate oxaloacetate transaminase (GOT) were increased in KDs and BTDs fed the diet containing 5 mg/kg of T-2 without GTP, respectively. However, duckling diets containing 5 mg/kg of T-2 with 0.5% GTP lowered concentrations of BUN and GOT in the blood plasma of KDs and BTDs, respectively. The diet containing 5 mg/kg of T-2 increased the relative kidney weight but decreased the relative breast weight of ducklings. Enlarged gizzards and reduced relative leg weights were observed in BTDs fed the diets containing 5 mg/kg of T-2. In summary, BTDs are more sensitive than KDs in responding to T-2 toxicity and GTP detoxification. Green tea powder has detoxification ability and could potentially mitigate T-2 toxicity on BWG, BUN, and GOT in ducklings.

A Metabolic Profiling Study of Realgar-Induced Acute Kidney Injury in Mice

Realgar has been used as a type of mineral drug that contains arsenic for thousands of years. Previous studies have shown that Realgar-induced acute kidney injury is associated with abnormal metabolism, but the underlying mechanism is poorly understood. The aim of this study is to investigate the metabolic changes in serum and kidney tissues of mice exposed to Realgar by using a metabolomic approach and explore the molecular mechanisms of acute kidney injury induced by Realgar. Forty mice were randomly divided into four groups: Control group, 0.5-, 1.0, and 2.0 g/kg Realgar group. After 1 week, the body weight and kidney weight of the mice were measured. The serum and kidney samples were used for LC-MS spectroscopic metabolic profiling. Principal component analysis (PCA), correlation analysis, and pathway analysis were used to detect the nephrotoxic effects of Realgar. Body weight decreased significantly in the 2.0 g/kg group, and the kidney weight index also showed a dose-dependent increase in Realgar. The PCA score plot showed the serum and kidney tissue metabolic profile of mice exposed to 2.0 g/kg Realgar separated from the control group, while the lower-doses of 0.5 g/kg and 1.0 g/kg Realgar shown a similar view to the Control group. Thirty-three metabolites and seventeen metabolites were screened and identified in the serum and kidney of mice in a dose-dependent manner. respectively. Correlation analysis showed a strong correlation among these metabolites. Amino acid metabolism, lipid metabolism, glutathione metabolism, and purine metabolism pathways were found to be mainly associated with Realgar nephrotoxicity. This work illustrated the metabolic alterations in Realgar-induced nephrotoxic mice through a metabolomic approach.

Yiqi Huoxue Recipe Regulates Autophagy through Degradation of Advanced Glycation End Products via mTOR/S6K1/LC3 Pathway in Diabetic Nephropathy

Background. Yiqi Huoxue recipe can delay the progression of diabetic nephropathy, but its treatment mechanism is still unclear. We aimed to explore the effects of Yiqi Huoxue recipe on autophagy in diabetic nephropathy and its underlying mechanism. Methods. All rats were randomly divided into seven groups. The body weight, kidney weight, blood glucose, glycated hemoglobin, urine protein, urine microprotein, creatinine, urea nitrogen, triglyceride, and lipoprotein were analyzed. HE, Masson, and periodic acid-Schiff staining were used to detect the severity of pathological changes in kidneys. The level of advanced glycation end products was assessed by the ELISA. Immunofluorescence staining was performed to check the expressions of podocin and nephrin. The expression levels of mTOR/S6K1/LC3 pathway-related proteins and mRNA were detected by qRT-PCR and western blotting. Results. Yiqi Huoxue recipe significantly elevated body weight and significantly decreased kidney weight and kidney index. Yiqi Huoxue recipe significantly affected the levels of biochemical indicators in diabetic nephropathy and showed a regulatory effect on kidney damage and lipid metabolism disorders. ELISA showed that Yiqi Huoxue recipe significantly reduced the level of advanced glycation end products. The expressions of nephrin and podocin increased significantly, depending on the dosage of Yiqi Huoxue recipe. Additionally, Yiqi Huoxue recipe regulated the expression levels of p-AKT, mTOR, S6K1, and LC3. Conclusion. Yiqi Huoxue recipe regulates podocyte autophagy to promote the degradation of advanced glycation end products through mTOR/S6K1/LC3 pathway. It has a certain guiding significance for the diagnosis and treatment of diabetic nephropathy.

Characterization of Enlarged Kidneys and Their Potential for Inducing Diabetes in DEK Rats

The kidneys participate in the regulation of systemic glucose metabolism via gluconeogenesis, insulin degradation, and the tubular reabsorption of glucose. The present study characterized rats from a strain of a novel type 2 diabetes model with enlarged kidneys (DEK). Histological and biochemical analyses of DEK rats were performed to assess the relationships between their kidneys and hyperglycemia. The kidney weight of diabetic DEK (DEK-DM) gradually increased over time from the onset of diabetes, with the glomerular number being higher in DEK-DM than in normal DEK (DEK-cont). A positive correlation between blood glucose level and kidney weight was observed in DEK-DM. The similar glomerular size and single glomerular creatinine clearance in DEK-cont and DEK-DM indicated that glomerular hypertrophy and hyperfiltration were not involved in the renal enlargement. Uninephrectomy (1/2Nx) in DEK-DM resulted in a reduction in blood glucose level at 7–28 post-operation days, with this concentration remaining lower than in Sham group until 84 days post-operation. 1/2Nx also improved systemic conditions, including reduced body weight gain, polyuria, polydipsia, and hyperphagia. Plasma concentrations of Na, total cholesterol, albumin, and total protein were higher, and urinary excretion of glucose, urea nitrogen, and proteins were lower, in the 1/2Nx than in the Sham group. Remnant kidney weight was two-fold higher in the 1/2Nx than in the Sham group 84 days later. In addition, 1/2Nx resulted in renal tubular dilatation but not in the progression of fibrosis or glomerular lesions. Taken together, these findings indicate that enlarged kidneys were associated with the onset of diabetes and with the resistance to diabetic nephropathy in DEK-DM.