Increase In Kidney Weight Research Articles

UJI AKTIVITAS ANTIDIABETES EKSTRAK DAUN PACAR AIR (Impatiens balsamina L.) TERHADAP GINJAL TIKUS WISTAR (Rattus novergicus L.) YANG DIINDUKSI ALOKSAN

Background: Diabetes mellitus is a serious, "chronic" condition that occurs when there is an increase in a person's blood sugar levels because the body is unable to produce enough insulin hormones/cannot effectively use the insulin produced. A lack of insulin, or the inability of cells to respond to it, causes high blood glucose levels (hyperglycemia), which causes clinical indicators of diabetes. Methods: This research is an experimental study using a completely randomized design. Twenty-four male white rats were divided into 6 groups consisting of normal controls (KN) who received no treatment, negative controls (K-) who were injected with alloxan at a dose of 150 mg/kg BW, positive controls (K+) who were injected with alloxan at a dose of 150 mg/kg BW. kg BW and glibenclamide at a dose of 0.09 mg/200 g BW, Treatment 1 (P1) was injected with alloxan at a dose of 150 mg/kg BW and ethanol extract of water henna leaves at a dose of 450 mg/KG BW, Treatment 2 (P2) was injected with alloxan with a dose of 150 mg/kg BW and ethanol extract of water henna leaves with a dose of 500 mg/KG BW, Treatment 3 (P3) was injected with alloxan at a dose of 150 mg/kg BW and ethanol extract of water henna leaves with a dose of 550 mg/KG BW. Mice blood glucose levels were measured on days 0 (after alloxan induction), 3, 7, and 14. Before the measurements, the mice were fasted for 8 hours. Results: Research shows that administration of water henna leaf extract has a significant effect in reducing urea and creatinine levels, as well as improving kidney morphology. However, it could not prevent the alloxan-induced increase in kidney weight in white mice. Conclusion: Administration of henna leaf extract (Impatiens balsamina L.) at a dose of 500 mg/kg BW had a significant effect on reducing urea and creatinine levels in white rats induced by alloxan. Administration of water henna leaf extract (Impatiens balsamina L.) at a dose of 450 mg/kg BW had a significant effect in improving kidney morphology in alloxan-induced white rats, whereas the organ index of water henna leaf extract could not prevent the increase in kidney weight in white mice induced alloxan

Acute and chronic effects of methanolic extract of Teucrium polium on blood parameters and histopathology of liver and kidney in Female Rats

Teucrium polium L. is commonly used as a medicinal plant in Algeria to fight various human diseases. In this study, extracting aerial parts of T. polium with methanol gave a dry matter yield of 8.24 %. The effects of methanolic extract of T. polium "TPME" were examined per os on female rats Albino Wistar for six weeks. Biochemical and hematological serum parameters and morphology and histopathology of organs of treated rats were studied. Acute toxicity showed low toxicity with a lethal dose of 50% LD50 > 2400 mg / Kg of body weight. These data can be used to classify these plants as slightly toxic. However, sub-acute treatment for six weeks of rats with 75, 150, and 300 mg of methanolic extract / Kg of body weight significantly increased the most studied hematological parameters. Biochemical analysis revealed a significant increase of renal parameters (urea, creatinine, uric acid, Na, and K), accompanied by an increase in the relative weight of kidney, lipidic (cholesterol), and hepatic glutamate oxaloacetate transaminase (GOT) values in all treated rats. Histopathological examination confirmed the biochemical tests by the observation of perilobular necrosis areas, bile duct and inflammatory infiltration of the liver, and the presence of marked intracytoplasmic vacuoles in the kidney with the dose 300 mg of TPME Kg of animal body weight. Use of Teucrium polium L. may cause hepatotoxicity and nephrotoxicity after prolonged herb administration. Keywords: Teucrium polium L, TPME, LD50, biochemical parameters, toxicity

Sex-specific modulation of renal epigenetic and injury markers in aging kidney.

Sex differences in renal physiology and pathophysiology are now well established in rodent models and in humans. Epigenetic programming is known to be a critical component of renal injury, as studied mainly in male rodent models; however, not much is known about the impact of biological sex and age on the kidney epigenome. We sought to determine the influence of biological sex and age on renal epigenetic and injury markers, using male and female mice at 4 mo (4M; young), 12 mo (12M), and 24 mo (24M; aged) of age. Females had a significant increase in kidney and body weights and serum creatinine levels and a decrease in serum albumin levels from 4M to 24M of age, whereas minor changes were observed in male mice. Kidney injury molecule-1 levels in serum and renal tissue greatly enhanced from 12M to 24M in both males and females. Circulating histone 3 (H3; damage-associated molecular pattern molecules) levels extensively increased with age; however, males had higher levels than females. Overall, females had markedly high histone acetyltransferase (HAT) activity than age-matched males. Aged mice had decreased HAT activity and increased histone deacetylase activity than sex-matched 12M mice. Aged females had substantially decreased renal H3 methylation at lysine 9 and 27 and histone methyltransferase (HMT) activity than aged male mice. Antiaging protein Klotho levels were significantly higher in young males than age-matched females and decreased substantially with age in males, whereas epigenetic repressor of Klotho, trimethylated H3K27, and its HMT enzyme, enhancer of zeste homolog 2, increased consistently with age in both sexes. Moreover, nuclear translocation and activity of proinflammatory transcription factor nuclear factor-κB (p65) were significantly higher in aged mice. Taken together, our data suggest that renal aging lies in a range between normal and diseased kidneys but may differ between female and male mice, highlighting sex-related differences in the aging process.NEW & NOTEWORTHY Although there is evidence of sex-specific differences in kidney diseases, most preclinical studies have used male rodent models. The clinical data on renal injury have typically not been stratified by sex. Our findings provide convincing evidence of sex-specific differences in age-regulated epigenetic alterations and renal injury markers. This study highlights the importance of including both sexes for better realization of underlying sex differences in signaling mechanisms of aging-related renal pathophysiology.

Sub-Chronic Toxicity Test of Purple Leaf Extract on the Kidney Histopathology of Male White Rats

Traditional herbal medicine has become increasingly popular as an alternative to conventional medical treatments. Although the plant offers numerous health benefits, caution should be exercised regarding its long-term use. Long-term use of traditional herbal remedies can have detrimental effects on the kidneys. This study was designed to assess the histological changes in the kidneys of male rats following 28 days of purple sage leaf extract administration and to identify potential harmful effects. The study utilized 20 male Wistar rats and utilized a randomized group design for the experimental methodology. Rats were categorized into four distinct groups, consisting of one control group and three treatment groups. The control group received solely sodium chloride, whereas the treatment group 1 (P1) received 500 mg/kg BB of purple sage ethanol extract. Treatment group 2 received up to 2000 mg/kg BB of purple sage ethanol extract, while treatment group 3 received up to 5000 mg/kg BB. The oral examination was conducted for a duration of 28 days. The treatment groups showed an increase in weight and organ index of the right kidney. The findings suggest a potential for toxicity resulting from the administration of purple sage leaf extract over a duration of 28 days.

Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone Improves Diastolic Dysfunction in Preclinical Nondiabetic Chronic Kidney Disease.

The mineralocorticoid receptor plays a significant role in the development of chronic kidney disease (CKD) and associated cardiovascular complications. Classic steroidal mineralocorticoid receptor antagonists are a therapeutic option, but their use in the clinic is limited due to the associated risk of hyperkalemia in patients with CKD. Finerenone is a nonsteroidal mineralocorticoid receptor antagonist that has been recently investigated in 2 large phase III clinical trials (FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO-DKD [Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease]), showing reductions in kidney and cardiovascular outcomes. We tested whether finerenone improves renal and cardiac function in a preclinical nondiabetic CKD model. Twelve weeks after 5/6 nephrectomy, the rats showed classic signs of CKD characterized by a reduced glomerular filtration rate and increased kidney weight, associated with left ventricular (LV) diastolic dysfunction and decreased LV perfusion. These changes were associated with increased cardiac fibrosis and reduced endothelial nitric oxide synthase activating phosphorylation (ser 1177). Treatment with finerenone prevented LV diastolic dysfunction and increased LV tissue perfusion associated with a reduction in cardiac fibrosis and increased endothelial nitric oxide synthase phosphorylation. Curative treatment with finerenone improves nondiabetic CKD-related LV diastolic function associated with a reduction in cardiac fibrosis and increased cardiac phosphorylated endothelial nitric oxide synthase independently from changes in kidney function. Short-term finerenone treatment decreased LV end-diastolic pressure volume relationship and increased phosphorylated endothelial nitric oxide synthase and nitric oxide synthase activity. We showed that the nonsteroidal mineralocorticoid receptor antagonist finerenone reduces renal hypertrophy and albuminuria, attenuates cardiac diastolic dysfunction and cardiac fibrosis, and improves cardiac perfusion in a preclinical nondiabetic CKD model.

Raising serum uric acid with a uricase inhibitor worsens PKD in rat and mouse models.

Humans are predisposed to gout because they lack uricase that converts uric acid to allantoin. Rodents have uricase, resulting in low basal serum uric acid. A uricase inhibitor raises serum uric acid in rodents. There were two aims of the study in polycystic kidney disease (PKD): 1) to determine whether increasing serum uric acid with the uricase inhibitor, oxonic acid, resulted in faster cyst growth and 2) to determine whether treatment with the xanthine oxidase inhibitor, oxypurinol, reduced the cyst growth caused by oxonic acid. Orthologous models of human PKD were used: PCK rats, a polycystic kidney and hepatic disease 1 (Pkhd1) gene model of autosomal recessive PKD (ARPKD) and Pkd1RC/RC mice, a hypomorphic Pkd1 gene model. In PCK rats and Pkd1RC/RC mice, oxonic acid resulted in a significant increase in serum uric acid, kidney weight, and cyst index. Mechanisms of increased cyst growth that were investigated were proinflammatory cytokines, the inflammasome, and crystal deposition in the kidney. Oxonic acid resulted in an increase in proinflammatory cytokines in the serum and kidney in Pkd1RC/RC mice. Oxonic acid did not cause activation of the inflammasome or uric acid crystal deposition in the kidney. In Pkd1RC/RC male and female mice analyzed together, oxypurinol decreased the oxonic acid-induced increase in cyst index. In summary, increasing serum uric acid by inhibiting uricase with oxonic acid results in an increase in kidney weight and cyst index in PCK rats and Pkd1RC/RC mice. The effect is independent of inflammasome activation or crystal deposition in the kidney.NEW & NOTEWORTHY This is the first reported study of uric acid measurements and xanthine oxidase inhibition in polycystic kidney disease (PKD) rodents. Raising serum uric acid with a uricase inhibitor resulted in increased kidney weight and cyst index in Pkd1RC/RC mice and PCK rats, elevated levels of proinflammatory cytokines in the serum and kidney in Pkd1RC/RC mice, and no uric acid crystal deposition or activation of the caspase-1 inflammasome in the kidney.

Hydroalcoholic Extract of Ziziphus Jujuba Leaf to Prevent Ethylene Glycol and Ammonium Chloride-Induced Kidney Stones in Male Rat: Is it Effective?

This study aimed to evaluate the effect of Ziziphus jujuba (Z. jujuba) leaf hydroalcoholic extract on the prevention/treatment of kidney stones. Thirty-six male Wistar rats were randomly divided into six groups: control, Sham (kidney stone induction (KSI) by ethylene glycol 1% + ammonium chloride 0.25% through drinking water for 28 days), Prevention groups 1, 2 (KSI and Z. jujuba leaf (250 and 500 mg/kg, respectively) through gavage for 28 days), and Treatment groups 1, 2 (KSI and Z. jujuba leaf (250 and 500 mg/kg, respectively) from the 15th day). On the 29th day, the rats' 24-hour urine was assessed, the animals were weighed, and blood samples were taken. Finally, after nephrectomy and weighing the kidneys, tissue sections were prepared to examine the number of calcium oxalate crystals and tissue changes. The results indicated a significant increase in kidney weight and index, tissue changes, and the number of calcium oxalate crystals in the Sham group compared to the control; using Z. jujuba leaf considerably reduced them in experimental groups compared to the Sham. Body weight decreased in the Sham and experimental groups (except the prevention 2 group) compared to the control, while this observed reduction was lower in all experimental groups compared to the Sham. The mean urinary calcium, uric acid, creatinine, and serum creatinine in Sham and experimental groups (except the prevention 2 group) indicated a substantial increase compared to the control and decreased significantly in all experimental groups compared to the Sham. Hydroalcoholic extract of Z. jujuba leaf is effective in the reduction of calcium oxalate crystals forming, and its most effective dose was 500mg/kg.

Toxicological Assessment of Higher Olefins in OECD TG 422 Repeated Dose and Reproductive /Developmental Toxicity Screening Tests in Han Wistar Rats.

Higher olefins (HO) are used primarily as intermediates in the production of other chemicals, such as polymers, fatty acids, plasticizer alcohols, surfactants, lubricants, amine oxides, and detergent alcohols. The potential toxicity of five HO (i.e., 1-Octene, Nonene, Decene, Hexadecene, and 1-Octadecene) with carbon ranging from C8 to C18 was examined in a combined repeated dose and reproduction/developmental toxicity screening study (OECD TG 422). These five HO were administered to Han Wistar rats by gavage at 0 (controls), 100, 300, and 1000mg/kg bw/day. As a group of substances, adaptive changes in the liver (liver weight increase without pathological evidence), as well as increased kidney weight in male rats, were observed in HO with carbon numbers from C8 to C10. The overall systemic no observed adverse effect level (NOAEL) for all HO was determined at 1000mg/kg bw/day. In the reproductive/developmental toxicity assessment, offspring viability, size, and weights were reduced in litters from females treated with Nonene at 1000mg/kg bw/day. The overall no observed effects level (NOEL) for reproductive toxicity was considered to be 300mg/kg bw/day for Nonene and 1000mg/kg bw/day for the other four HO, respectively. These data significantly enrich the database on the toxicity of linear and branched HO, allowing comparison with similar data published on a range of linear and branched HO. Comparisons between structural class and study outcome provide further supportive data in order to validate the read-across hypothesis as part of an overall holistic testing strategy.

Human Nephrogenesis can Persist Beyond 40 Postnatal Days in Preterm Infants

IntroductionHuman nephrogenesis is typically completed by 36 weeks (wks) gestation, but impacted by preterm birth. Early studies suggested that nephrogenesis persisted for ≤ 40 postnatal days in preterm infants. However, the postmenstrual age (PMA) of the preterm infants who survived > 40 days was uncertain. In this study, we sought to re-examine postnatal kidney development in preterm infants surviving > 40 days. MethodsHuman kidney samples were obtained from an institutional biobank. Samples were considered controls if survival was ≤ 4 days after birth with PMA of 30 to ≤ 36 wks. Kidneys from preterm neonates with postnatal survival > 40 days and PMA of 30 to ≤ 36 wks were compared to controls. We counted glomerular generations, measured nephrogenic zone widths, and performed immunofluorescence (IF) with SIX1 and RET. We compared kidney weights and quantified the cross-sectional area of proximal (LTL, SL22A2), distal (SLC12A3, KCNJ10), and glomerular (nephrin) markers using IF. ResultsSeven preterm infants surviving > 40 days and 8 controls were analyzed. 4/7 preterm infants had histologic and molecular evidence of nephrogenesis. Cessation of nephrogenesis in preterm infants occurred two weeks earlier than PMA-matched controls with attenuated expression of both SIX1 and RET. We found increased kidney weight: body weight ratio, increased distal tubular cross-sectional staining in the superficial nephrons, and distal tubular hypertrophy/hyperplasia in the preterm infant kidneys. ConclusionOur study supports that nephrogenesis in preterm infants persists longer than previously thought with evidence of early nephron stress, placing importance on the neonatal environment.

Modulatory effects of extract of Heinsia crinita against fructose/streptozotocin-induced oxidative stress in diabetic rat models

Oxidative stress plays a crucial role in the development of type 2 diabetes and the associated microvascular and cardiovascular complications. In the study, we have investigated the effects of Heinsia crinita (H. crinita) extracts on lipid peroxidation and oxidative stress responses using diabetic rats. Type 2 diabetes was induced with 10 % fructose/40 mg/kg body weight streptozotocin (STZ). H. crinita extract was administered at 200 and 400 mg/kg body weight twice daily for 21 days, in addition to metformin (MET: 500 mg/kg body weight) control. Molecular docking analysis was performed to determine the binding affinity of H. crinita extracts to the DNA binding domains of peroxisome proliferator-activated receptor (Ppar) and retinoid x receptor (Rxr) protein crystal structures, showing different binding affinities for putative active compounds from the plant. Fasting blood glucose (FBG), body and organ weight changes were determined showing that H. crinita extract induced an anti-hyperglycemic effect in the treated animals, with changes (either decrease or increase) in liver and kidney weights. A decrease in mRNA expression of peroxisome proliferator-activated receptors (ppar), sterol regulatory element-binding protein 1 (srebp-1c), liver x-receptor (lxr), retinoid x receptors (rxr), cytochrome p45041 (cyp4a1) and acyl-CoA oxidase (acox1) in diabetic animals were observed, compared to the control. A dose-specific decrease or increase in antioxidant enzymes (superoxide dismutase: SOD, catalase: CAT, reduced glutathione: GSH, glutathione peroxidase: GPx) transcripts and activity levels were also observed. We also observed exposure-specific decrease or increase of malondialdehyde (MDA) levels. Our data suggested that H. crinita extract possesses protective effects against diabetes-induced oxidative stress. These effects might be attributed to their binding and activation of nuclear receptors, indicating their cellular mode of action that is comparable to MET.

Abstract 080: The Non-steroidal Mineralocorticoid Receptor Antagonist Finerenone Improves Diastolic Dysfunction In Preclinical Non-diabetic Chronic Kidney Disease

Background: The mineralocorticoid receptor (MR) plays an important role in the development of Chronic Kidney Disease (CKD) and its overactivation contributes to the progression of cardiovascular complications. Antagonizing the overactivation of the MR with MR antagonists (MRA) is a therapeutic option. Finerenone, is a non-steroidal MRA recently studied in two large clinical trials showing the beneficial effects lowering the risks of CKD progression and cardiovascular events in stage 1 to 4 CKD patients with type 2 diabetes (T2D) (FIDELIO-DKD and FIGARO-DKD trials) Aim: To test whether finerenone improves renal and/or cardiac functions in preclinical non-diabetic CKD. Methods: non-diabetic CKD was induced by 5/6 nephrectomy in 6 weeks old Sprague Dawley rats. Finerenone (10 mg/kg/day) was administered as preventive or as curative treatment. Left ventricle (LV) function/hemodynamics, LV tissue perfusion and GFR were assessed in vivo at the age of 24 weeks. Results: 12 weeks after 5/6 nephrectomy, the rats showed classical signs of CKD: reduced GFR and increased kidney weight; associated with LV diastolic dysfunction confirmed by increased in LV end-diastolic pressure (LVEDP), LV relaxation constant (Tau) and LV end-diastolic pressure volume-relation (LVEDPVR), while LV perfusion was reduced. Both prevention and curative treatment with finerenone reduced significantly both LVEDPVR and Tau; and increased LV tissue perfusion. Finerenone treatment did not impact reduced kidney GFR but reduced renal hypertrophy. Conclusion: Both preventive and curative finerenone improves non-diabetic CKD related LV diastolic function, independently from changes in kidney function.

Bee Venom Causes Oxidative Stress, Biochemical and Histopathological Changes in the Kidney of Mice.

Accidents with venomous bees are a serious worldwide health concern. Since the kidney has been reported as the main venom-target organ, the present study was undertaken to investigate the in vivo nephrotoxic effect of Algerian bee venom (ABV) (Apis mellifera intermissa) collected in the middle east of Algeria. A preliminary study was performed on ABV to identify the ABV using SDS-PAGE analysis and to determine the in vivo intraperitoneal median lethal dose (LD50) using the Probit analysis test. In vivo nephrotoxic effect was assessed through the determination of physiological and kidney biochemical markers in mice intraperitoneally injected with ABV at doses of 0.76 (D1); 1.14 (D2) and 2.29 mg/kg body weight (bwt) (D3), corresponding respectively to LD50/15, LD50/10, and LD50/5 (i.p. LD50=11.48 mg/kg bwt) for seven consecutive days. Results revealed a marked decrease in body weight gain and food intake, and an increase in absolute and relative kidney weights in ABV D2 and D3 treated mice compared with controls. Furthermore, ABV D2 and D3 resulted in a significant increase in serum creatinine, urea, and uric acid. ABV-induced oxidative stress was evidenced by a significant increase in kidney MDA level, and a significant depletion in kidney GSH level, and catalase activity. Meanwhile, no marked changes in the above-mentioned parameters were noticed in ABV D1. Accordingly, the adverse nephrotoxic effect of ABV was proved by the dose-dependent kidney histological changes. In summary, the results of the present study evidence that ABV at doses of 1.14 (D2) and 2.28 mg/kg body weight (bwt) can cause marked changes in kidney biochemical and major antioxidant markers, and histological architecture.

Accelerated cystogenesis by dietary protein load is dependent on, but not initiated by kidney macrophages.

Disease severity of autosomal dominant polycystic kidney disease (ADPKD) is influenced by diet. Dietary protein, a recognized cyst-accelerating factor, is catabolized into amino acids (AA) and delivered to the kidney leading to renal hypertrophy. Injury-induced hypertrophic signaling in ADPKD results in increased macrophage (MФ) activation and inflammation followed by cyst growth. We hypothesize that the cystogenesis-prompting effects of HP diet are caused by increased delivery of specific AA to the kidney, ultimately stimulating MФs to promote cyst progression. Pkd1flox/flox mice with and without Cre (CAGG-ER) were given tamoxifen to induce global gene deletion (Pkd1KO). Pkd1KO mice were fed either a low (LP; 6%), normal (NP; 18%), or high (HP; 60%) protein diet for 1 week (early) or 6 weeks (chronic). Mice were then euthanized and tissues were used for histology, immunofluorescence and various biochemical assays. One week fed kidney tissue was cell sorted to isolate tubular epithelial cells for RNA sequencing. Chronic dietary protein load in Pkd1KO mice increased kidney weight, number of kidney infiltrating and resident MФs, chemokines, cytokines and cystic index compared to LP diet fed mice. Accelerated cyst growth induced by chronic HP were attenuated by liposomal clodronate-mediated MФ depletion. Early HP diet fed Pkd1KO mice had larger cystic kidneys compared to NP or LP fed counterparts, but without increases in the number of kidney MФs, cytokines, or markers of tubular injury. RNA sequencing of tubular epithelial cells in HP compared to NP or LP diet group revealed increased expression of sodium-glutamine transporter Snat3, chloride channel Clcnka, and gluconeogenesis marker Pepck1, accompanied by increased excretion of urinary ammonia, a byproduct of glutamine. Early glutamine supplementation in Pkd1KO mice lead to kidney hypertrophy. Chronic dietary protein load-induced renal hypertrophy and accelerated cyst growth in Pkd1KO mice is dependent on both infiltrating and resident MФ recruitment and subsequent inflammatory response. Early cyst expansion by HP diet, however, is relient on increased delivery of glutamine to kidney epithelial cells, driving downstream metabolic changes prior to inflammatory provocation.

Isolation, Purification, Structural Characterization, and Hypoglycemic Activity of Polysaccharide from Trichosanthes kirilowii Maxim. Seed Shell

In this manuscript, polysaccharide (TMSP) was isolated from Trichosanthes kirilowii Maxim. seed shell. The homogeneous polysaccharide (TMSP-1; molecular weight: 690.239 kDa) was purified by column chromatography (DEAE-cellulose-52 and Sephadex G-150). The result of monosaccharide composition showed that TMSP-1 consisted of D-mannose, D-glucose, D-galactose, and glucuronic acid in a molar ratio of 2.01 : 1.98 : 1.87 : 1. Methylation analysis showed that TMSP-1 was made up of →3)-D-Galp-(1→, D-Glcp-(1→, →4)-D-Manp-(1→, →6)-D-Galp-(1→, →4)-D-Galp-(1→, and →4,6)-D-Manp-(1→. The microscopic conformation of TMSP-1 showed a regular flake-like structure that was inlaid with small holes. The α-glucosidase inhibitory rate of TMSP-1 reached 52.23% when the concentration of TMSP-1 was 8 mg/mL, which confirmed the potential hypoglycemic activity of TMSP-1 in vitro. In vivo results showed that type 2 diabetes causes a significant increase in organ index and TMSP-1 recovered the organ index in mice ( P < 0.05 ). Furthermore, TMSP-1 reversed the increase of liver and kidney weight and the indicators of abnormality. This research lays a foundation for research on the polysaccharides of Trichosanthes kirilowii Maxim. seed shell in hypoglycemia.

Leptin-dependent gene expression and function in mouse kidney

Objective: Leptin regulates energy balance via leptin receptor expressed in central and peripheral tissues. Little is known about leptin receptor (Lepr)-mediated kidney gene expression and function. Here, we determined kidney gene expression of Lepr splice variants, leptin-sensitive kidney gene expression, and the role of Lepr in renal tubular cells for the response to a high fat diet. Methods: A) Four groups of male mice were used for urine/plasma analysis, and kidney cortex RNA-seq and quantitative RT-PCR (qPCR) analysis: BTBR wild-type, BTBR ob/ob-vehicle (BTBR background in ob/ob promotes diabetic kidney disease), BTBR ob/ob-chronic leptin replacement [6 days via osmotic mini-pump, 4.7 μg/day], and BTBR ob/ob-acute leptin replacement [single dose of 5 mg/kg body weight i.p. and analysis after 7 hours]; all 12-19 weeks old; n=4~15/group. B) Tubular Lepr knockdown (Pax8-Lepr KO) mice were generated by the Pax8-Cre/loxP system, and 5-week old male Pax8-Lepr KO and littermate control mice (n=8-12/group) were fed either control diet or high fat diet (60 kcal% fat) for 35 weeks. Lepr in situ hybridization and qPCR were performed in kidney tissue, and physiological parameters and urinary albumin to creatinine ratio (UACR) were determined. Results: qPCR analysis of Lepr splice variants A, B and C in BTBR mouse kidney revealed a ratio of ~100:10:1 in cortex and medulla with medullary levels being ~10x higher vs cortex with little effects of leptin deficiency (ob/ob)/or replacement. Chronic leptin replacement in ob/ob mice reduced hyperphagia, hyperglycemia and albuminuria, associated with normalization of kidney mRNA expression of molecular markers of glycolysis, gluconeogenesis, amino acid synthesis and megalin. Acute leptin replacement was ineffective implicating indirect metabolic effects for albuminuria in leptin deficiency. Tubular knockdown of Lepr and in situ hybridization indicated that a minor fraction of kidney Lepr mRNA is expressed by tubular cells compared with interstitial or endothelial cells. Nonetheless, Pax8-Lepr KO mice had 13% lower kidney weight (P=0.038). Moreover, they presented similar high fat diet-induced increases in plasma leptin levels, body and kidney weight, and GFR vs controls but a 50% reduced rise in UACR (P=0.0005). Two additional leptin or tubular Lepr-sensitive genes were identified: Leptin deficiency and tubular Lepr knockdown reduced renal expression of acetoacetyl-CoA synthetase (AACS) and increased expression of gremlin 1 (Grem1), while leptin replacement in ob/ob induced opposite effects. Conclusions: Leptin deficiency may increase albuminuria via systemic metabolic effects that impinge on kidney megalin expression. Hyperleptinemia-induced albuminuria may involve direct effects via tubular Lepr. Implications of the novel tubular Lepr/AACS/Grem1 axis and of Lepr variants remain to be determined. This study was supported by Janssen Pharmaceuticals, Inc. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Empagliflozin increases kidney weight due to increased cell size in the proximal tubule S3 segment and the collecting duct.

The inhibition of renal SGLT2 glucose reabsorption has proven its therapeutic efficacy in chronic kidney disease. SGLT2 inhibitors (SGLTi) have been intensively studied in rodent models to identify the mechanisms of SGLT2i-mediated nephroprotection. So far, the overwhelming effects from clinical trials, could only partially be reproduced in rodent models of renal injury. However, a commonly disregarded observation from these studies, is the increase in kidney weight after SGLT2i administration. Increased kidney mass often relies on tubular growth in response to reabsorption overload during glomerular hyperfiltration. Since SGLT2i suppress hyperfiltration but concomitantly increase renal weight, it seems likely that SGLT2i have a growth promoting effect on the kidney itself, independent of GFR control. This study aimed to investigate the effect of SGLT2i on kidney growth in wildtype animals, to identify enlarged nephron segments and classify the size increase as hypertrophic/hyperplastic growth or cell swelling. SGLT2i empagliflozin increased kidney weight in wildtype mice by 13% compared to controls, while bodyweight and other organs were not affected. The enlarged nephron segments were identified as SGLT2-negative distal segments of proximal tubules and as collecting ducts by histological quantification of tubular cell area. In both segments protein/DNA ratio, a marker for hypertrophic growth, was increased by 6% and 12% respectively, while tubular nuclei number (hyperplasia) was unchanged by empagliflozin. SGLT2-inhibition in early proximal tubules induces a shift of NaCl resorption along the nephron causing compensatory NaCl and H2O reabsorption and presumably cell growth in downstream segments. Consistently, in collecting ducts of empagliflozin-treated mice, mRNA expression of the Na+-channel ENaC and the H2O-channels Aqp-2/Aqp-3 were increased. In addition, the hypoxia marker Hif1α was found increased in intercalated cells of the collecting duct together with evidence for increased proton secretion, as indicated by upregulation of carbonic anhydrases and acidified urine pH in empagliflozin-treated animals. In summary, these data show that SGLT2i induce cell enlargement by hypertrophic growth and possibly cell swelling in healthy kidneys, probably as a result of compensatory glucose, NaCl and H2O hyperreabsorption of SGLT2-negative segments. Particularly affected are the SGLT2-negative proximal tubules (S3) and the collecting duct, areas of low O2 availability.

The protective impact of glutamine on anti-tuberculosis drug-induced nephrotoxicity in Wistar rats

This study assessed the protective effect of glutamine (GTN) against rifampicin/isoniazid/pyrazinamide/ethambutol (RIPE)-induced nephrotoxicity in rats. Thirty adult Wistar rats (200±20 g) of both sexes were grouped into 6 of 5 rats/group. The rats were treated daily for 30 days as follows: Group 1 (Vehicle control [normal saline 0.2mL]), group 2 (GTN 200 mg/kg), group 3 (RIPE 150, 75, 400 and 275 mg/kg in vehicle), group 4 (GTN 50 mg/kg +RIPE), group 5 (GTN 100 mg/kg +RIPE) and group 6 (GTN 200 mg/kg +RIPE). After treatment, blood samples were obtained and assessed for serum renal biomarkers. Kidneys were harvested, weighed and assessed for oxidative stress markers and histology. RIPE significantly (p<0.01) decreased body weight and significantly (p<0.01) increased kidney weight when compared to the control. Serum urea, creatinine, uric acid levels and kidney malondialdehyde levels were significantly (p<0.001) increased in RIPE-treated rats when compared to the control. Serum total protein, albumin, kidney glutathione, catalase, superoxide dismutase and glutathione peroxidase levels were significantly decreased (p<0.001) in RIPE-treated rats when compared to the control. RIPE caused tubular necrosis and collapsed glomeruli in the kidneys of rats. However, body and liver weights were significantly restored in GTN 100 mg/kg +RIPE and GTN 200 mg/kg +RIPE-treated rats at p<0.05 and p<0.01, respectively when compared to RIPE. Serum and kidney oxidative stress markers were restored in GTN 50 mg/kg +RIPE, GTN 100 mg/kg +RIPE and GTN 200 mg/kg +RIPE-treated rats at p<0.05, p<0.01 and p<0.001 respectively, when compared to RIPE. GTN restored kidney histology. GTN protects against RIPE-induced nephrotoxicity in a dose-related fashion.

Lead exposure induced developmental nephrotoxicity in Japanese quail (Coturnix japonica) via oxidative stress-based PI3K/AKT pathway inhibition and NF-κB pathway activation

Birds are sensitive to environmental pollution and lead (Pb) contamination could negatively affect nearly all avian organs and systems including kidney of excretive system. Thereby, we used a biological model species-Japanese quail (Coturnix japonica) to examine the nephrotoxic effects of Pb exposure and possible toxic mechanism of Pb on birds. Quail chicks of 7-day-old were exposed to 50 ppm Pb of low dose and high dose of 500 ppm and 1000 ppm Pb in drinking water for five weeks. The results showed that Pb exposure induced kidney weight increase while body weight and length reduction. The increase of uric acid (UA), creatinine (CREA) and cystatin c (Cys C) in the plasma suggested renal dysfunction. Moreover, both microstructural and ultrastructural changes demonstrated obvious kidney damages. In particular, renal tubule epithelial cells and glomeruli swelling indicated renal inflammation. Furthermore, changes in the content and activity of oxidative stress markers suggested that Pb caused excessive oxidative stress in the kidney. Pb exposure also induced abnormal apoptosis in the kidney. In addition, RNA sequencing (RNA-Seq) analysis revealed that Pb disturbed molecular pathways and signaling related with renal function. Especially, Pb exposure resulted in an increase in renal uric acid synthesis by disrupting purine metabolism. Pb caused apoptotic increment by inhibiting the phosphatidylinositol-3-kinase (PI3K)/RAC-alpha serine/threonine-protein kinase (AKT) pathway and induced aggravated inflammation by activating Nuclear Factor kappa B (NF-κB) signaling pathway. The study implied that Pb caused nephrotoxicity through structural damages, uric acid metabolism disorder, oxidation imbalance, apoptosis and inflammatory pathway activation.

Protective Effects Of Vitis vinifera And Carica papaya Seed Extracts On Diclofenac-Alcohol Combination Induced Kidney Damage In Albino Rats

Diclofenac is a non-steroidal anti-inflammatory drug commonly used in the treatment of pain and inflammatory conditions in the tropics. Its easy accessibility without prescription has made it a commonly abused medication. The abuse has recently become worrisome as young adults in Nigeria have been observed to concomitantly use diclofenac and alcohol for non-medical purpose. This study was undertaken to study the nephrotoxic effect associated with the combine use of alcohol and diclofenac using animal model, and the protective effect of Vitis vinifera (Grape) seed and Carica papaya (pawpaw) seed. Adult albino rats were divided randomly into groups of six rats each, and each group treated for 90 days with 5% or 45% alcohol with 2mg/kg diclofenac or 10mg/kg diclofenac, and some rats treated with grape seed and/or pawpaw seed concomitantly. Diclofenac and 45% alcohol combination induced nephrotoxicity in rats and oxidative stress characterised by elevated serum urea and creatinine, increased malondialdehyde and decrease in reduced glutathione, catalase and superoxide dismutase in kidney homogenate, as well as moderate interstitial congestion and haemorrhage in rat kidney histology section stained with Haematoxylin and Eosin, which was significantly ameliorated by the grape seed and pawpaw seed. There was a 1.32% increase in relative kidney weight in comparison with control rats. The severity of the nephrotoxicity observed with diclofenac-alcohol combination makes it a very unsafe practice. There is need to explore the nephroprotective benefits of Vitis vinifera seed and Carica papaya seed for maximum benefit to man.

A histological investigation of the influence of Naringin on acetaminophen-induced nephrotoxicity in male albino rats

A study was conducted to examine the protective effects of naringin (NRG) on renal tissues of rats, specifically against acetaminophen (ACN)-induced damage. Thirty-two male rats were included in the study, divided into four groups. The first group (group I) was administered 1 ml/kg of saline orally, serving as the control group. The second group received 2g/kg of ACN on the first day. The third group received a single oral dose of 2g/kg of ACN on the first day, followed by 40 mg/kg of oral NRG for eight consecutive days. Lastly, the fourth group was given a single oral dose of 2g/kg of ACN on the first day, followed by 80 mg/kg of oral NRG for eight days. The rats were then euthanized and their kidneys were removed after they had been anesthetized for blood collection. The ACN-induced renal damage was characterized by significant reductions in body weight, levels of superoxide dismutase (SOD), and catalase. Additionally, there were significant increases in kidney weight, serum creatinine, blood urea nitrogen, serum uric acid, malondialdehyde enzyme (MAD), and histopathological alterations. The study demonstrated that NRG treatment at doses of 40 and 80 mg/kg b.w. effectively reduced renal toxicity and oxidative damage induced by ACN. The effectiveness of these improvements was demonstrated by the noticeable increase in body weight, elevated levels of SOD and CAT, as well as the reduction in kidney weight, CR, BUN, SUA, and MAD levels. As a result of these findings, NRG is confirmed to have antioxidant properties and be capable of protecting rats from renal toxicity caused by ACN.