美国生理学杂志 - 肾脏生理学发表关于基础科学和临床研究的及时主题的原始手稿。已发表的文章涉及与肾脏和泌尿道相关的广泛主题，可能涉及人类或动物模型、单个细胞类型和分离的膜系统。还涵盖了肾脏疾病过程的病理生理学基础、体液调节以及提供机制见解的临床研究。可以使用广泛的方法进行肾功能研究，例如生物化学、免疫学、遗传学、数学建模、分子生物学以及生理学和临床方法。

The American Journal of Physiology - Renal Physiology publishes original manuscripts on timely topics in basic science and clinical research related to the kidneys and urinary tract. Published articles cover a wide range of subjects, potentially involving human or animal models, individual cell types, and isolated membrane systems. The journal also addresses the pathophysiological basis of kidney disease processes, fluid regulation, and clinical studies that provide mechanistic insights. Various methods can be employed for renal function research, including biochemistry, immunology, genetics, mathematical modeling, molecular biology, as well as physiological and clinical approaches.

《American Journal of Physiology - Renal Physiology》发表关于基础科学和临床研究的原创性文章，涵盖与肾脏及泌尿系统相关的广泛主题。这些研究可能涉及人类或动物模型、单个细胞类型以及分离的膜系统。期刊还探讨肾脏疾病的病理生理学基础、体液调节，以及提供机制见解的临床研究。肾功能研究的方法多种多样，包括生物化学、免疫学、遗传学、数学建模、分子生物学，以及生理学和临床方法。

American Journal of Physiology - Renal Physiology

Improving drug delivery to the kidney using renal-targeted therapeutics is a promising but underdeveloped area. We aimed to develop a kidney-targeting construct for renal-specific drug delivery. Elastin-like polypeptides (ELPs) are nonimmunogenic protein-based carriers that can stabilize attached small-molecule and peptide therapeutics. We modified ELP at its NH2-terminus with a cyclic, seven-amino acid kidney-targeting peptide (KTP) and at its COOH-terminus with a cysteine residue for tracer conjugation. Comparative in vivo pharmacokinetics and biodistribution in rat and swine models and in vitro cell binding studies using human renal cells were performed. KTP-ELP had a longer plasma half-life than ELP in both animal models and was similarly accumulated in kidneys at levels fivefold higher than untargeted ELP, showing renal levels 15- to over 150-fold higher than in other major organs. Renal fluorescence histology demonstrated high accumulation of KTP-ELP in proximal tubules and vascular endothelium. Furthermore, a 14-day infusion of a high dose of ELP or KTP-ELP did not affect body weight, glomerular filtration rate, or albuminuria, or induce renal tissue damage compared with saline-treated controls. In vitro experiments showed higher binding of KTP-ELP to human podocytes, proximal tubule epithelial, and glomerular microvascular endothelial cells than untargeted ELP. These results show the high renal selectivity of KTP-ELP, support the notion that the construct is not species specific, and demonstrate that it does not induce acute renal toxicity. The plasticity of ELP for attachment of any class of therapeutics unlocks the possibility of applying ELP technology for targeted treatment of renal disease in future studies.

Gene L. Bidwell

Fakhri Mahdi

Qingmei Shao

Omar C. Logue

Jamarius P. Waller

Caleb Reese

Alejandro R. Chade

AJP Renal Physiology

A kidney-selective biopolymer for targeted drug delivery

一种用于靶向药物递送的肾脏选择性生物聚合物

Acute kidney injury (AKI) is a common clinical state resulting from pathogenic conditions such as ischemic and toxic insults. The pathophysiology of AKI shares common pathogenic denominators including cell death/injury, inflammation, and fibrosis, regardless of the initiating insults. Recent clinical studies have shown that a single episode of AKI can lead to subsequent chronic kidney disease (CKD). Although the involvement of multiple types of cells in the pathophysiology of AKI is becoming increasingly clear, the precise mechanisms for this “AKI to CKD progression” are still unknown, and no drug has been shown to halt this progression. An increasing number of epidemiological studies have also revealed that the presence of aging greatly increases the risk of AKI to CKD progression, and chronic inflammation is increasingly recognized as an important determinant factor for this progression. In this review article, we first describe the current understanding of the pathophysiology of AKI to CKD progression based on multiple types of cells. In particular, we will highlight the recent findings in regard to the mechanisms for chronic inflammation after AKI. Subsequently, we will focus on the mechanisms responsible for the increased risk of AKI to CKD progression in the elderly. Finally, we highlight our recent finding of age-dependent tertiary lymphoid tissue formation and its roles in AKI to CKD progression and speculate on the potential therapeutic opportunities that come from targeting aberrant inflammation after AKI.

Yuki Sato

Motoko Yanagita

American Journal of Physiology-Renal Physiology

Immune cells and inflammation in AKI to CKD progression

免疫细胞与炎症在急性肾损伤向慢性肾病进展中的作用

Mitochondria are essential organelles in the human body, serving as the metabolic factory of the whole organism. When mitochondria are dysfunctional, it can affect all organs of the body. The kidney is rich in mitochondria, and its function is closely related to the development of kidney diseases. Studying the relationship between mitochondria and kidney disease progression is of great interest. In the past decade, scientists have made inspiring progress in investigating the role of mitochondria in the pathophysiology of renal diseases. This article discusses various mechanisms for maintaining mitochondrial quality, including mitochondrial energetics, mitochondrial biogenesis, mitochondrial dynamics, mitochondrial DNA repair, mitochondrial proteolysis and the unfolded protein response, mitochondrial autophagy, mitochondria-derived vesicles, and mitocytosis. The article also highlights the cross talk between mitochondria and other organelles, with a focus on kidney diseases. Finally, the article concludes with an overview of mitochondria-related clinical research.

Yuxian Guo

Ruochen Che

Peipei Wang

Aihua Zhang

Mitochondrial dysfunction in the pathophysiology of renal diseases

肾病病理生理学中的线粒体功能障碍

After spinal cord injury (SCI), the neurogenic bladder is observed to develop asynchronous bladder and external urethral sphincter (EUS) contractions in a condition known as detrusor-sphincter dyssnergia (DSD). Activation of the EUS spinal controlling center located at the upper lumbar spinal cord may contribute to reduce EUS dyssynergic contractions and decrease urethral resistance during voiding. However, this mechanism has not been well studied. This study aimed at evaluating the effects of epidural stimulation (EpS) over the spinal EUS controlling center (L3) in combination with a serotonergic receptor agonist on EUS relaxation in naive rats and chronic (6–8 wk) T8 SCI rats. Cystometrogram and EUS electromyography (EMG) were obtained before and after the intravenous administration of 5HT-1A receptor agonist and antagonist. The latency, duration, frequency, amplitude, and area under curve of EpS-evoked EUS EMG responses were analyzed. EpS on L3 evoked an inhibition of EUS tonic contraction and an excitation of EUS intermittent bursting/relaxation correlating with urine expulsion in intact rats. Combined with a 5HT-1A receptor agonist, EpS on L3 evoked a similar effect in chronic T8 SCI rats to reduce urethral contraction (resistance). This study examined the effect of facilitating the EUS spinal controlling center to switch between urine storage and voiding phases by using EpS and a serotonergic receptor agonist. This novel approach of applying EpS on the EUS controlling center modulates EUS contraction and relaxation as well as reduces urethral resistance during voiding in chronic SCI rats with DSD.

Edsel M. Abud

Ronaldo M. Ichiyama

Leif A. Havton

Huiyi H. Chang

Spinal stimulation of the upper lumbar spinal cord modulates urethral sphincter activity in rats after spinal cord injury

脊髓损伤后大鼠上腰椎脊髓刺激调节尿道括约肌活动

Increasing evidence suggests that chronic kidney disease may develop following acute kidney injury and that this may be due, in part, to hypoxia-related phenomena. Hypoxia-inducible factor (HIF) is stabilized in hypoxic conditions and regulates multiple signaling pathways that could contribute to renal fibrosis. As transforming growth factor (TGF)-β is known to mediate renal fibrosis, we proposed a profibrotic role for cross talk between the TGF-β1 and HIF-1α signaling pathways in kidney cells. Hypoxic incubation increased HIF-1α protein expression in cultured human renal tubular epithelial cells and mouse embryonic fibroblasts. TGF-β1 treatment further increased HIF-1α expression in cells treated with hypoxia and also increased HIF-1α in normoxic conditions. TGF-β1 did not increase HIF-1α mRNA levels nor decrease the rate of protein degradation, suggesting that it enhances normoxic HIF-1α translation. TGF-β receptor (ALK5) kinase activity was required for increased HIF-1α expression in response to TGF-β1, but not to hypoxia. A dominant negative Smad3 decreased the TGF-β-stimulated reporter activity of a HIF-1α-sensitive hypoxia response element. Conversely, a dominant negative HIF-1α construct decreased Smad-binding element promoter activity in response to TGF-β. Finally, blocking HIF-1α transcription with a biochemical inhibitor, a dominant negative construct, or gene-specific knockdown decreased basal and TGF-β1-stimulated type I collagen expression, while HIF-1α overexpression increased both. Taken together, our data demonstrate cooperation in signaling between Smad3 and HIF-1α and suggest a new paradigm in which HIF-1α is necessary for normoxic, TGF-β1-stimulated renal cell fibrogenesis.

Rajit K. Basu

Susan Hubchak

Tomoko Hayashida

Constance E. Runyan

Paul T. Schumacker

H. William Schnaper

Interdependence of HIF-1α and TGF-β/Smad3 signaling in normoxic and hypoxic renal epithelial cell collagen expression

常氧和缺氧肾上皮细胞胶原表达中HIF-1α与TGF-β/Smad3信号的相互依赖性

The presence of tubular casts within the kidney serves as an important feature when assessing the degree of renal injury. Quantification of renal tubular casts has been historically difficult due varying cast morphologies, protein composition, and stain uptake properties, even within the same kidney. Color thresholding remains one of the most common methods of quantification in the laboratory when assessing the percentage of renal casting; however, this method is unable to account for tubule casts stained a variety of colors. We have developed a novel method of automated cast quantification using the machine learning pixel classification tool within QuPath, an open-source software designed for digital pathology. We demonstrated the usability of this method in male and female Dahl SS rats fed either low or high salt for two weeks and male Sprague Dawley rats treated with podotoxin puromycin aminonucleoside (PAN). Briefly, the pixel classifier was trained to identify kidney tissue, various cast color types, and slide background. Following development of the pixel classifier, we applied it to the sample population and compared the results with those of other methods of cast quantification including color thresholding and manual quantification. We found that the automated pixel classifier designed in QuPath was able to comprehensively quantify metachromatic tubular casts compared to color thresholding. This novel method of cast quantification provides researchers with the ability to reliably automate cast quantification that is both comprehensive and efficient.

Lauren Yunker

Megan Cleland Harwig

Alison J. Kriegel

A Novel Automated Method for Comprehensive Renal Cast Quantification from Rat Kidney Sections using QuPath

一种基于QuPath的大鼠肾脏切片中肾小管管型全面自动定量新方法

Why fibroblast growth factor 23 (FGF23) levels increase markedly in chronic kidney disease (CKD) is unknown. Recently, we found that phosphate stimulates renal production of glycerol-3-phosphate (G-3-P), which circulates to bone to trigger FGF23 production. To assess the impact of G-3-P on FGF23 production in CKD, we compared the effect of adenine-induced CKD in mice deficient in glycerol-3-phosphate dehydrogenase 1 (Gpd1), an enzyme that synthesizes G-3-P, along with wild-type littermates. We find that adenine diet causes a similar degree of renal insufficiency across genotype and that adenine-induced CKD increases blood G-3-P and FGF23 levels in wild-type mice. Further, we find that the increase in both G-3-P and FGF23 are significantly attenuated, but not fully abrogated, in Gpd1−/− compared to Gpd1+/+ mice with CKD. There is no difference in blood phosphate or PTH between Gpd1−/− and Gpd1+/+ mice on adenine diet, but adenine-induced CKD causes greater cortical bone loss in Gpd1−/− mice. In a separate cohort of rats fed an adenine or control diet, we confirm that CKD causes an increase in blood G-3-P levels. Importantly, an acute phosphate load increases G-3-P production in both CKD and non-CKD rats, with a significant correlation between measured kidney phosphate uptake and blood G-3-P levels. Together, these findings establish a key role for G-3-P in mineral metabolism in CKD, although more work is required to parse the factors that regulate both Gpd1-dependent and Gpd1-independent G-3-P production in this context.

Petra Simic

Han Xie

Qian Zhang

Wen Zhou

Rohan Cherukuru

Michael A Adams

Mandy E Turner

Eugene P Rhee

Glycerol-3-phosphate contributes to the increase in FGF23 production in chronic kidney disease

甘油-3-磷酸在慢性肾脏病中促进FGF23生成增加的作用

SGLT2 inhibitors (SGLT2i) and GLP1 receptor (GLP1R) agonists have kidney protective effects. To better understand their molecular effects, RNA sequencing was performed in SGLT2-positive proximal tubule segments isolated by immunostaining-guided laser capture microdissection. Male adult DBA wildtype (WT) and littermate diabetic Akita mice ± Sglt1 knockout (Sglt1-KO) were given vehicle or SGLT2i dapagliflozin (dapa; 10mg/kg diet) for 2 weeks, and other Akita mice received GLP1R agonist semaglutide (sema; 3nmol/[kg body weight*day], s.c.). Dapa (254±11mg/dL) and Sglt1-KO (367±11mg/dL) but not sema (407±44mg/dL) significantly reduced hyperglycemia in Akita mice (480±33mg/dL). The 20,748 detected annotated protein-coding genes included robust enrichment of S1-segment marker genes. Akita showed 198 (~1%) differentially expressed genes vs. WT (DEGs; adjusted p<0.1) including downregulation of anionic transport, unsaturated fatty acid and carboxylic acid metabolism. Dapa changed only 2 genes in WT but restored 43% of DEGs in Akita, including upregulation of lipid metabolic pathway, carboxylic acid metabolism and organic anion transport. In Akita, sema restored ~10% of DEGs, and Sglt1-KO and dapa were synergistic (restored ~61%) possibly involving additive blood glucose effects (193±15mg/dl). Targeted analysis of transporters and channels (t-test p<0.05) revealed that ~10% of 526 detectable transporters and channels were downregulated by Akita, with ~60% restored by dapa. Dapa, dapa+Sglt1-KO and sema also altered Akita-insensitive genes. Among DEGs in Akita, ~30% were unresponsive to any treatment, indicating potential new targets. In conclusion, SGLT2i restored transcription for multiple metabolic pathways and transporters in SGLT2-positive proximal tubule segments in diabetic mice, with a smaller effect also observed for GLP1R agonism.

Young Chul Kim

Vivek Das

Sadhana Kanoo

Huazhen Yao

Stephanie M. Stanford

Nunzio Bottini

Anil Karihaloo

Volker Vallon

Transcriptomics of SGLT2-positive early proximal tubule segments in mice: response to type 1 diabetes, SGLT1/2 inhibition, or GLP1 receptor agonism

小鼠SGLT2阳性早期近端小管段的转录组学：对1型糖尿病、SGLT1/2抑制或GLP1受体激动作用的反应

Glomerular endothelial cell (GEnC) injury is a common feature across the wide spectrum of glomerular diseases. We recently reported that the endothelial-specific knockout of Krüppel-like factor 4 (Klf4) increases the susceptibility to GEnC injury and subsequent development of subacute thrombotic microangiopathy (TMA). However, the mechanism(s) mediating GEnCs response to injury in TMA are poorly understood. Single nucleus RNA sequencing demonstrated an enrichment in pathways involved in angiogenesis, permeability, focal adhesion, dedifferentiation and cytoskeletal organization in the endothelial cluster in mice with TMA. Plasmalemmal vesicle-associated protein (Plvap), a structural component of fenestral diaphragms, was highly enriched specifically in injured GEnCs. Induction of Plvap in cultured GEnCs increased proliferation, migration and cell permeability with an accompanying loss of mature GEnC markers. Immunostaining for PLVAP in human kidney biopsies confirmed the increase in glomerular PLVAP in TMA, which correlated with a higher grade of glomerular injury. To date, this is the first study to show that the induction of Plvap in GEnCs shifts the cells to an immature state, which might exacerbate glomerular injury in TMA.

Chelsea C Estrada

Craig Wilson

Nehaben Gujarati

Sumaya Ahmed

Robert Bronstein

Ilse S. Daehn

Monica P. Revelo

Yiqing Guo

Sandeep K. Mallipattu

Induction of Plasmalemmal vesicle-associated protein exacerbates glomerular endothelial injury in thrombotic microangiopathy.

质膜小泡相关蛋白的诱导加剧了血栓性微血管病中的肾小球内皮损伤。

New treatments to slow kidney disease progression and reduce cardiovascular disease risk are needed for chronic kidney disease (CKD). We investigated the cholesterol-lowering PCSK9 inhibitor alirocumab as a new treatment for proteinuric CKD and the effect of SGLT2 inhibition using empagliflozin in obese ZSF1 rats. Regarding renoprotection, our findings were contradictory with previous preclinical studies and clinical data, suggesting that different pathophysiological mechanisms may apply to this rat model.

Sandra Hummelgaard

Henning Hvid

Henrik Birn

Simon Glerup

Nikola Tom

Mesut Bilgin

Jeppe Egedal Kirchhoff

Kathrin Weyer

Lack of renoprotective effects by long-term PCSK9 and SGLT2 inhibition using alirocumab and empagliflozin in obese ZSF1 rats

长期使用阿利珠单抗和恩格列净抑制PCSK9和SGLT2在肥胖ZSF1大鼠中缺乏肾脏保护作用

Abbreviation
Journal Impact	3.88
Quartiles(Global)	UROLOGY & NEPHROLOGY(Q1)

ISSN	1931-857X
h-index	190

Publication Information	Publisher: American Physiological Society，Publishing cycle: Monthly，Journal Type: journal，Open Access Journals: No
Basic data	Year of publication: 1992，Proportion of original research papers: 91.43%，Self Citation Rate:10.80%， Gold OA Rate: 5.00%
Average review cycle	网友分享经验：较快,2-4周
Average recruitment ratio	网友分享经验：较难

American Journal of Physiology - Renal Physiology

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