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HMGB1 drives T-cell activation in hypertensive males and females.
Pub Date : 2025-04-01 Epub Date: 2025-02-21 DOI: 10.1152/ajprenal.00197.2024
Elizabeth C Snyder, Riyaz Mohamed, Jennifer C Sullivan

We previously published that hypertensive males have greater renal necrosis and a more pro-inflammatory immune profile than females. Hypertension causes the release of damage-associated molecular patterns (DAMPs), which stimulate inflammation. The goal of the current study was to determine if high-mobility group box 1 (HMGB1), a well-characterized DAMP, contributes to greater T-cell activation in hypertensive males versus females and normotensive controls of both sexes. To test this hypothesis, initial studies measured renal and plasma HMGB1 levels in 13-wk-old male and female spontaneously hypertensive rats (SHRs) and Wistar Kyoto (WKY) rats by Western blot and ELISA. Total renal CD3+ T-cells and IL-6+ cells were measured by flow cytometry. The contribution of HMGB1 to T-cell activation was measured in isolated renal T-cells via mixed lymphocyte reaction (MLR) in the presence of control IgG or anti-HMGB1 neutralizing antibody. Plasma HMGB1 levels were greater in male SHRs compared with those in female SHR and WKY rats of both sexes. Renal HMGB1 levels were higher in SHR than in WKY and tended to be greater in males versus females in both strains. Consistent with this finding, T-cell activation and renal interleukin (IL)-6 were highest in male SHR. Interestingly, anti-HMGB1 antibody treatment decreased T-cell activation to the same extent in male and female SHRs, with negligible effects on WKY. These results indicate a role for HMGB1 in T-cell activation in SHR. However, despite male SHR having greater levels of HMGB1 than females, HMGB1 does not account for sex differences in T-cell activation.NEW & NOTEWORTHY There is growing evidence that T-cells contribute to both the development of hypertension and sex differences in blood pressure control. Our work establishes the damage-associated molecular pattern HMGB1 as an important contributor to T-cell activation in hypertension.

我们曾发表文章指出,与女性相比,男性高血压患者的肾脏坏死程度更高,其免疫特征也更趋于炎症性。高血压会导致损伤相关分子模式(DAMPs)的释放,从而刺激炎症。本研究的目的是确定高迁移率组盒 1(HMGB1)这一特征明显的 DAMP 是否会导致男性高血压患者与女性高血压患者以及正常血压的男女对照组相比,T 细胞活化程度更高。为了验证这一假设,最初的研究采用 Western 印迹法和 ELISA 法测量了 13 周大的雄性自发性高血压大鼠(SHR)和雌性 Wistar Kyoto(WKY)大鼠的肾脏和血浆 HMGB1 水平。流式细胞术测量了肾脏 CD3+ T 细胞和 IL-6+ 细胞的总量。在对照 IgG 或抗 HMGB1 中和抗体存在的情况下,通过混合淋巴细胞反应 (MLR) 测定离体肾 T 细胞中 HMGB1 对 T 细胞活化的贡献。与雌性 SHR 和 WKY 相比,雄性 SHR 的血浆 HMGB1 水平更高。SHR的肾脏HMGB1水平高于WKY,而且在这两个品系中,雄性肾脏HMGB1水平往往高于雌性肾脏HMGB1水平。与这一发现相一致的是,雄性 SHR 的 T 细胞活化和肾 IL-6 水平最高。有趣的是,抗 HMGB1 抗体治疗可在相同程度上降低雄性 SHR 和雌性 SHR 的 T 细胞活化,而对 WKY 的影响可忽略不计。这些结果表明,HMGB1 在 SHR 的 T 细胞活化中发挥作用。然而,尽管雄性 SHR 的 HMGB1 水平高于雌性,但 HMGB1 并不能解释 T 细胞活化的性别差异。
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引用次数: 0
TNF inhibits NKCC2 phosphorylation by a calcineurin-dependent pathway.
Pub Date : 2025-03-10 DOI: 10.1152/ajprenal.00251.2024
Shoujin Hao, Anna Pia Lasaracina, Jarred Epps, Nicholas R Ferreri

We previously demonstrated that TNF inhibits NKCC2 phosphorylation in the thick ascending limb (TAL); however, the underlying mechanism remains unclear. We tested the hypothesis that the induction of calcineurin (CN) activity and the expression of CN isoforms contribute to the mechanism by which TNF inhibits phospho-NKCC2 (pNKCC2) expression. CN activity increased by approximately 2-fold in primary cultures of medullary (m)TAL cells challenged with mouse recombinant TNF. In contrast, silencing TNF production in mTAL cells using lentivirus U6-TNF-ex4 reduced CN activity. pNKCC2 expression decreased in mTAL cells challenged with TNF whereas inhibition of CN activity with cyclosporine A (CsA) increased pNKCC2 expression. Although mTAL cells express both the calcineurin A subunit (CNA) a and b isoforms, only CNA b isoform mRNA increased after mTAL cells were challenged with TNF. In vivo, both TNF and CNA b expression increased in outer medulla (OM) from mice given 1% NaCl in the drinking water for 7 days and intrarenal lentivirus silencing of TNF selectively reduced expression of CNA b. Intrarenal injection of a lentivirus that specifically silenced CNA b (U6-CNAb-ex6) increased pNKCC2 expression and attenuated the inhibitory effects of TNF on pNKCC2 expression in freshly isolated TAL tubules. Collectively, the study is the first to demonstrate that TNF increases CN activity and specifically induces β-isoform expression in the kidney. Since NKCC2 is a known target of the CNA b isoform, these findings suggest that a CN-dependent signaling pathway involving this isoform contributes to the mechanism by which TNF inhibits pNKCC2 expression.

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引用次数: 0
Lysine acetylation of aquaporin-3 promotes water permeability but is not essential for urine concentrating ability.
Pub Date : 2025-03-10 DOI: 10.1152/ajprenal.00037.2025
Nha V Huynh, Luciano D Mendoza, Hung Nguyen, Cassidy Rehage, Elizabeth B Saurage, Parker Davis, Kelly A Hyndman

Aquaporin-3 (AQP3) mediates basolateral water transport in the kidney principal cells contributing to urine concentration. We previously identified the acetylation of lysine 282 (K282) in the C-terminus of AQP3, which we hypothesized as a positive regulator of AQP3 water permeability. AQP3 acetylation (K282Q or Q), or deacetylation (K282R or R) mimetic mutant mice models were created using CRISPR/Cas9. Male and female wild-type (WT) and mutant mice were assigned to hydrating diets and water deprivation protocols. Urine and plasma osmolality in response to acute vasopressin receptor-2 activation with desmopressin (dDAVP) or inhibition by tolvaptan were determined. In vitro water permeability of murine principal kidney cortical collecting duct (mpkCCD) cells stably expressing AQP3 WT, Q, or R was measured. Acetylated AQP3 was prominent in the cortical to inner medullary collecting ducts of dehydrated versus hydrated mice. At baseline the mutations did not affect the kidney transcriptome, AQP3 abundance, nor subcellular localization. Urine osmolality of the mutant mice was within the normal range. With dehydration, all mice excreted a concentrated urine; however, the female Q mutants exhibited significantly greater 24 h urine osmolality than WT, suggesting greater water reabsorption. In response to acute dDAVP, all mice produced a concentrated urine; however, female Q mutants had a more dilute plasma than WT, further suggesting greater water retention. mpkCCD Q mutant cells exhibited greater water permeability than WT and R cells. We conclude that AQP3 K282 acetylation promotes principal cell water permeability in a sex-dependent manner, however, it is not essential for urine concentration.

{"title":"Lysine acetylation of aquaporin-3 promotes water permeability but is not essential for urine concentrating ability.","authors":"Nha V Huynh, Luciano D Mendoza, Hung Nguyen, Cassidy Rehage, Elizabeth B Saurage, Parker Davis, Kelly A Hyndman","doi":"10.1152/ajprenal.00037.2025","DOIUrl":"https://doi.org/10.1152/ajprenal.00037.2025","url":null,"abstract":"<p><p>Aquaporin-3 (AQP3) mediates basolateral water transport in the kidney principal cells contributing to urine concentration. We previously identified the acetylation of lysine 282 (K282) in the C-terminus of AQP3, which we hypothesized as a positive regulator of AQP3 water permeability. AQP3 acetylation (K282Q or Q), or deacetylation (K282R or R) mimetic mutant mice models were created using CRISPR/Cas9. Male and female wild-type (WT) and mutant mice were assigned to hydrating diets and water deprivation protocols. Urine and plasma osmolality in response to acute vasopressin receptor-2 activation with desmopressin (dDAVP) or inhibition by tolvaptan were determined. <i>In vitro</i> water permeability of murine principal kidney cortical collecting duct (mpkCCD) cells stably expressing AQP3 WT, Q, or R was measured. Acetylated AQP3 was prominent in the cortical to inner medullary collecting ducts of dehydrated versus hydrated mice. At baseline the mutations did not affect the kidney transcriptome, AQP3 abundance, nor subcellular localization. Urine osmolality of the mutant mice was within the normal range. With dehydration, all mice excreted a concentrated urine; however, the female Q mutants exhibited significantly greater 24 h urine osmolality than WT, suggesting greater water reabsorption. In response to acute dDAVP, all mice produced a concentrated urine; however, female Q mutants had a more dilute plasma than WT, further suggesting greater water retention. mpkCCD Q mutant cells exhibited greater water permeability than WT and R cells. We conclude that AQP3 K282 acetylation promotes principal cell water permeability in a sex-dependent manner, however, it is not essential for urine concentration.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
CRB2 Depletion Induces YAP Signaling and Disrupts Mechanosensing in Podocytes.
Pub Date : 2025-03-10 DOI: 10.1152/ajprenal.00318.2024
Yingyu Sun, Nils M Kronenberg, Sidharth Sethi, Surjya N Dash, Maria E Kovalik, Benjamin Sempowski, Shelby Strickland, Rupesh Raina, C John Sperati, Xuefei Tian, Shuta Ishibe, Gentzon Hall, Malte C Gather

Focal Segmental Glomerulosclerosis (FSGS) is a histologic lesion caused by a variety of injurious stimuli that lead to dysfunction/loss of glomerular visceral epithelial cells (i.e. podocytes). Pathogenic mutations in CRB2, encoding the type 1 transmembrane protein crumbs homolog-2, have been shown to cause early-onset corticosteroid-resistant nephrotic syndrome (SRNS)/FSGS. Here, we identified a 2-generation Indian kindred (DUK40595) with biopsy-proven SRNS/FSGS caused by a compound heterozygous mutation in CRB2 comprised of the previously described truncating mutation p.Gly1036_Alafs*43 and a rare 9-bp deletion mutation p.Leu1074_Asp1076del. Because compound heterozygous mutations involving the truncating p.Gly1036_Alafs*43 variant have been associated with reduced CRB2 expression in podocytes and autosomal recessive SRNS/FSGS, we sought to define the pathogenic effects of CRB2 deficiency in podocytes. We show that CRB2 knockdown induces YAP activity and target gene expression in podocytes. It upregulates YAP-mediated mechanosignaling and increases the density of focal adhesion and F-actin. Using elastic resonator interference stress microscopy (ERISM), we demonstrate that CRB2 knockdown also enhances podocyte contractility in a substrate stiffness-dependent manner. The knockdown effect decreases with increasing substrate stiffness, indicating impaired mechanosensing in CRB2 knockdown cells at low substrate stiffness. While the mechanical activation of CRB2 knockdown cells is associated with increased YAP activity, the enhanced cell contractility is not significantly reduced by the selective YAP inhibitors K-975 and verteporfin, suggesting that multiple pathways may be involved in mechanosignaling downstream of CRB2. Taken together, these studies provide the first evidence that CRB2 deficiency may impair podocyte mechanotransduction via disruption of YAP signaling in podocytes.

{"title":"CRB2 Depletion Induces YAP Signaling and Disrupts Mechanosensing in Podocytes.","authors":"Yingyu Sun, Nils M Kronenberg, Sidharth Sethi, Surjya N Dash, Maria E Kovalik, Benjamin Sempowski, Shelby Strickland, Rupesh Raina, C John Sperati, Xuefei Tian, Shuta Ishibe, Gentzon Hall, Malte C Gather","doi":"10.1152/ajprenal.00318.2024","DOIUrl":"https://doi.org/10.1152/ajprenal.00318.2024","url":null,"abstract":"<p><p>Focal Segmental Glomerulosclerosis (FSGS) is a histologic lesion caused by a variety of injurious stimuli that lead to dysfunction/loss of glomerular visceral epithelial cells (i.e. podocytes). Pathogenic mutations in CRB2, encoding the type 1 transmembrane protein crumbs homolog-2, have been shown to cause early-onset corticosteroid-resistant nephrotic syndrome (SRNS)/FSGS. Here, we identified a 2-generation Indian kindred (DUK40595) with biopsy-proven SRNS/FSGS caused by a compound heterozygous mutation in CRB2 comprised of the previously described truncating mutation p.Gly1036_Alafs*43 and a rare 9-bp deletion mutation p.Leu1074_Asp1076del. Because compound heterozygous mutations involving the truncating p.Gly1036_Alafs*43 variant have been associated with reduced CRB2 expression in podocytes and autosomal recessive SRNS/FSGS, we sought to define the pathogenic effects of CRB2 deficiency in podocytes. We show that CRB2 knockdown induces YAP activity and target gene expression in podocytes. It upregulates YAP-mediated mechanosignaling and increases the density of focal adhesion and F-actin. Using elastic resonator interference stress microscopy (ERISM), we demonstrate that CRB2 knockdown also enhances podocyte contractility in a substrate stiffness-dependent manner. The knockdown effect decreases with increasing substrate stiffness, indicating impaired mechanosensing in CRB2 knockdown cells at low substrate stiffness. While the mechanical activation of CRB2 knockdown cells is associated with increased YAP activity, the enhanced cell contractility is not significantly reduced by the selective YAP inhibitors K-975 and verteporfin, suggesting that multiple pathways may be involved in mechanosignaling downstream of CRB2. Taken together, these studies provide the first evidence that CRB2 deficiency may impair podocyte mechanotransduction via disruption of YAP signaling in podocytes.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Effect of sex chromosome complement versus gonadal hormones on abundance of renal transporters.
Pub Date : 2025-03-10 DOI: 10.1152/ajprenal.00017.2025
Alicia A McDonough, Trinity S Foley, Donna L Ralph, Seth Schwindt, Joanne Soong, Rolando Carrisoza Gaytan, Samia Lasaad, Jonathan W Nelson, Aurelie Edwards, Thomas R Kleyman, Lisa M Satlin

Sex differences in renal tubular salt and water transporters, channels, claudins and regulatory factors are evident all along the nephron. The influence of sex hormones on physiologic dimorphisms has been established in studies removing, inhibiting or restoring sex hormones and their receptors. The influence of the sex chromosome complement (SCC, XY vs. XX) on renal transporter abundance and activity is an open question. We employed the Four Core Genotypes (FCG) mouse model (in which the testis determining SRY gene is deleted from the Y chromosome and inserted onto an autosomal chromosome) to compare abundance of more than fifty renal transporters and regulators in: FXX gonadal females, FXY gonadal females, MXX Sry males, and MXY XYSry males using semi-quantitative immunoblots. In addition to establishing the significant influence of gonadal hormones, we show, for the first time, that SCC contributes to sexual dimorphisms in abundance of renal transporters including: NHE3, SGLT1 and 2, AQP1, mNKAα1 and β1, NCC, and ENaC β and γ subunits. The findings in this FCG model analysis provide the foundation for future studies of the role of sex hormones vs. chromosomes on physiologic parameters including filtration and flow, on transporter covalent modifications, and trafficking in both heath and disease.

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引用次数: 0
Fueling Kidney Recovery: Boosting BCAA Metabolism to Overcome Nephrotoxic AKI.
Pub Date : 2025-03-06 DOI: 10.1152/ajprenal.00024.2025
Pinelopi Kapitsinou
{"title":"Fueling Kidney Recovery: Boosting BCAA Metabolism to Overcome Nephrotoxic AKI.","authors":"Pinelopi Kapitsinou","doi":"10.1152/ajprenal.00024.2025","DOIUrl":"https://doi.org/10.1152/ajprenal.00024.2025","url":null,"abstract":"","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Nicotinamide ameliorates podocyte injury and albuminuria in adriamycin-induced nephropathy.
Pub Date : 2025-03-04 DOI: 10.1152/ajprenal.00297.2024
Kei Takahashi, Emiko Sato, Seiko Yamakoshi, Mizuki Ogane, Akiyo Sekimoto, Takamasa Ishikawa, Kiyomi Kisu, Yuji Oe, Koji Okamoto, Mariko Miyazaki, Tetsuhiro Tanaka, Nobuyuki Takahashi

Podocytes are key components of the glomerular filtration barrier, and their injury leads to proteinuria, chronic kidney disease (CKD), and nephrotic syndrome. Effective treatments for these conditions are not well established, and prevention of podocyte injury is a crucial challenge. Nicotinamide (NAM), a form of vitamin B3, has been reported to exert beneficial effects in various renal disease models due to its antioxidant and anti-inflammatory properties and its ability to replenish nicotinamide adenine dinucleotide (NAD+). However, its impact on adriamycin (ADR)-induced nephropathy, a model of nephrotic syndrome caused by podocyte injury, remains unclear. We investigated the effects of NAM administration in a mouse model of ADR nephropathy. BALB/c mice were intravenously administered ADR to induce nephropathy. In the NAM-treated group, mice received 0.6% NAM in drinking water ad libitum starting 7 days before ADR administration. After 14 days, NAM treatment decreased albuminuria, glomerular sclerosis, and podocyte injury, and reduced inflammation and oxidative stress markers in the kidneys. NAM and NAD+ levels were decreased in ADR-treated kidneys, and the expression of the NAD+-consuming enzymes SIRT1 and PARP-1 was decreased and increased, respectively. Nicotinamide N-methyltransferase expression was increased. NAM canceled these abnormalities. In cultured rat podocytes, NAD+ alleviated ADR-induced cytotoxicity, apoptosis, and inflammation. These findings suggest that NAM prevents ADR nephropathy and podocyte injury, likely through NAD+ replenishment.

{"title":"Nicotinamide ameliorates podocyte injury and albuminuria in adriamycin-induced nephropathy.","authors":"Kei Takahashi, Emiko Sato, Seiko Yamakoshi, Mizuki Ogane, Akiyo Sekimoto, Takamasa Ishikawa, Kiyomi Kisu, Yuji Oe, Koji Okamoto, Mariko Miyazaki, Tetsuhiro Tanaka, Nobuyuki Takahashi","doi":"10.1152/ajprenal.00297.2024","DOIUrl":"https://doi.org/10.1152/ajprenal.00297.2024","url":null,"abstract":"<p><p>Podocytes are key components of the glomerular filtration barrier, and their injury leads to proteinuria, chronic kidney disease (CKD), and nephrotic syndrome. Effective treatments for these conditions are not well established, and prevention of podocyte injury is a crucial challenge. Nicotinamide (NAM), a form of vitamin B3, has been reported to exert beneficial effects in various renal disease models due to its antioxidant and anti-inflammatory properties and its ability to replenish nicotinamide adenine dinucleotide (NAD<sup>+</sup>). However, its impact on adriamycin (ADR)-induced nephropathy, a model of nephrotic syndrome caused by podocyte injury, remains unclear. We investigated the effects of NAM administration in a mouse model of ADR nephropathy. BALB/c mice were intravenously administered ADR to induce nephropathy. In the NAM-treated group, mice received 0.6% NAM in drinking water ad libitum starting 7 days before ADR administration. After 14 days, NAM treatment decreased albuminuria, glomerular sclerosis, and podocyte injury, and reduced inflammation and oxidative stress markers in the kidneys. NAM and NAD<sup>+</sup> levels were decreased in ADR-treated kidneys, and the expression of the NAD<sup>+</sup>-consuming enzymes SIRT1 and PARP-1 was decreased and increased, respectively. Nicotinamide N-methyltransferase expression was increased. NAM canceled these abnormalities. In cultured rat podocytes, NAD<sup>+</sup> alleviated ADR-induced cytotoxicity, apoptosis, and inflammation. These findings suggest that NAM prevents ADR nephropathy and podocyte injury, likely through NAD<sup>+</sup> replenishment.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143544901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The impact of maternal obesity on polycystic kidney disease progression in a mouse model. 母体肥胖对小鼠模型多囊肾进展的影响
Pub Date : 2025-03-01 Epub Date: 2025-02-05 DOI: 10.1152/ajprenal.00227.2024
Sarah J Miller, Kaitlyn Hill, Isabella Darby, Fariha Nusrat, Jacob E Friedman, Michael C Rudolph, Kurt A Zimmerman

Due to the growing obesity epidemic in the United States, it is now estimated that approximately one third of all children are born to obese moms. These data, coupled with data indicating that obesity is associated with accelerated cyst growth in patients with autosomal dominant polycystic kidney disease (ADPKD), led us to hypothesize that maternal obesity may influence the rate of disease progression in offspring. To test this hypothesis, we induced maternal obesity by high-fat diet (HFD) feeding in the orthologous Pkd1RC/RC mouse model of ADPKD and followed polycystic kidney disease (PKD) progression in offspring for up to 1 year. Surprisingly, and in contrast to our initial hypothesis, exposure to maternal obesity during pregnancy and lactation did not significantly impact PKD severity in offspring at 3 mo or 1 yr of age. In contrast, reexposure to HFD for ∼3 m beginning at 12 wk of age worsened PKD severity in female, but not male, offspring born to obese dams as measured by cystic index, cyst number, and cyst area. Despite worsened cystic parameters, fibrosis and blood urea nitrogen were not altered in these animals. Collectively, these findings indicate that maternal obesity may accelerate PKD severity in female offspring exposed to an obesogenic diet.NEW & NOTEWORTHY Due to the growing obesity pandemic, almost one third of all children are born to mothers with obesity; however, the impact of maternal obesity on polycystic kidney disease (PKD) is unknown. In this manuscript, we found that maternal obesity did not worsen PKD severity in Pkd1RC/RC mice at 3 mo or 1 yr of age when weaned onto normal chow diet. However, rechallenging pups born to obese mothers worsened PKD severity in female but not male mice.

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引用次数: 0
Chronic kidney disease amplifies severe kidney injury and mortality in a mouse model of skin arsenical exposure. 在皮肤接触砷的小鼠模型中,慢性肾病会加重严重肾损伤并导致死亡。
Pub Date : 2025-03-01 Epub Date: 2024-10-17 DOI: 10.1152/ajprenal.00139.2024
Ritesh Kumar Srivastava, Amie Mark Traylor, Suhail Muzaffar, Stephanie K Esman, Reham H Soliman, Jasim Khan, Phoebe Warren, Subhashini Bolisetty, James F George, Anupam Agarwal, Mohammad Athar

In previously published work, we elucidated the role of cutaneous arsenical exposure in promoting acute kidney injury (AKI) in adult healthy mice. Here, we determine whether preexisting chronic kidney disease (CKD) increases the severity of AKI. Following exposure to aristolochic acid (AA) (a nephrotoxic phytochemical in humans), mice manifested classical markers of CKD, including robust interstitial fibrosis and loss in kidney function. Skin challenge with phenylarsine oxide (PAO), a surrogate for warfare arsenicals, led to significantly worse kidney injury, as evidenced by tubulointerstitial fibrosis, glomerulosclerosis, a persistent loss of estimated glomerular filtration rate, and mortality in AA-induced CKD mice compared with mice without CKD. These PAO-challenged CKD mice exhibited enhanced production of serum/urine neutrophil gelatinase-associated lipocalin and a significant rise in serum creatinine along with histological markers of kidney injury, including brush border loss, tubular atrophy, cast formation, glomerular injury, and interstitial inflammatory cell infiltration. Serum cytokines IL-4, IL-6, IFN-γ, IL-12p70, TNF-α, and IL-18 significantly elevated in CKD mice following PAO exposure when compared with animals exposed to PAO alone. Furthermore, we found increased TUNEL-positive tubular cells in the kidneys of CKD mice following PAO exposure, suggesting enhanced PAO-mediated cell death in CKD mice. Mechanistically, we determined that DNA damage-regulated p53 signaling was a major mediator of cellular responses to PAO in CKD mice. In summary, our data demonstrate that CKD significantly increased the severity of AKI following exposure to arsenicals and suggest that human populations with preexisting CKD could be highly susceptible to arsenical-mediated kidney injury and associated morbidity and mortality.NEW & NOTEWORTHY Preexisting chronic kidney disease (CKD) predisposes experimental animals to augmented morbidity and mortality following cutaneous vesicant exposure. The mechanism underlying increased susceptibility to renal injury and associated morbidity involves the DNA damage-regulated p53 signaling pathway.

在以前发表的研究中,我们阐明了皮肤砷暴露在促进成年健康小鼠急性肾损伤(AKI)中的作用。在这里,我们要确定已有的慢性肾病(CKD)是否会增加急性肾损伤的严重程度。小鼠暴露于马兜铃酸(AA)(一种对人类具有肾毒性的植物化学物质)后,表现出典型的 CKD 标志,包括肾间质纤维化和肾功能丧失。与未患 CKD 的小鼠相比,AA 诱导的 CKD 小鼠皮肤受到战争砷的替代物苯基氧化砒霜(PAO)的挑战后,肾脏损伤明显加重,表现为肾小管间质纤维化、肾小球硬化、估计肾小球滤过率持续下降和死亡。这些受到 PAO 挑战的 CKD 小鼠表现出血清/尿液 NGAL 生成增加、血清肌酐显著升高以及肾脏损伤的组织学标志物,包括刷状缘缺失、肾小管萎缩、铸型形成、肾小球损伤和间质炎症细胞浸润。与单独暴露于 PAO 的小鼠相比,暴露于 PAO 的 CKD 小鼠血清细胞因子 IL-4、IL-6、IFN-γ、IL-12p70、TNF-α 和 IL-18 明显升高。此外,我们还发现,暴露于 PAO 后,CKD 小鼠肾脏中 TUNEL 阳性的肾小管细胞增多,这表明 PAO 在 CKD 小鼠体内介导的细胞死亡增强。从机理上讲,我们确定 DNA 损伤调控的 p53 信号转导是 CKD 小鼠细胞对 PAO 反应的主要介质。总之,我们的数据表明,CKD 会显著增加接触砷化物后发生 AKI 的严重程度,这也表明预先存在 CKD 的人群极易受到砷化物介导的肾损伤以及相关的发病率和死亡率的影响。
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引用次数: 0
Looking below the surface: using intravital imaging to decipher inflammatory renal disease and renal cell injury.
Pub Date : 2025-03-01 Epub Date: 2025-02-07 DOI: 10.1152/ajprenal.00321.2024
Michael J Hickey, Vaishnavi Sudhakar

Renal function can be perturbed by a range of stimuli that cause cellular injury and inflammation in the kidney. These injurious and inflammatory processes are typically dynamic and progressive, involving the actions of highly migratory cells such as leukocytes and cellular responses that occur over time spans ranging from seconds to weeks. Understanding these dynamic responses has entailed the use of imaging technologies that allow visualization and capture of events over different time spans, ideally in intact organs in live, experimental animals. The technique that allows this is intravital imaging. Intravital imaging, particularly multiphoton intravital microscopy, has been crucial to the investigation of dynamic physiological and pathophysiological processes in the kidney for many years, driving key developments in our understanding of renal (patho)physiology. This includes the mechanisms of ultrafiltrate generation, the response to acute kidney injury, and how inflammatory leukocytes are recruited to and cause injury in the kidney. This review describes the key studies that have applied intravital imaging to the investigation of models of inflammatory renal disease. The responses examined include those restricted to the glomerulus and the effects of acute kidney injury on the tubulointerstitium. Future innovations and directions in this field of research are also discussed.

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引用次数: 0
期刊
American journal of physiology. Renal physiology
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