American Journal Of Physiology. Renal Physiology[JOURNAL]
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200 papers
Influence of carnosine supplementation on disease progression in a rat model of focal segmental glomerulosclerosis.
Xu X, Pastene DO, Qiu J … +6 more , Schnell B, Maihöfer T, Hettler S, Krämer BK, Hoffmann S, Yard BA
Am J Physiol Renal Physiol · 2025 Apr · PMID 40079823 · Publisher ↗
In diabetic kidney disease models, carnosine supplementation ameliorates renal pathology, but its influence in other renal pathologies is less explored. Thus, using the transgenic rat TGRNeph-hAT1 with sex-dependent foca...
In diabetic kidney disease models, carnosine supplementation ameliorates renal pathology, but its influence in other renal pathologies is less explored. Thus, using the transgenic rat TGRNeph-hAT1 with sex-dependent focal segmental glomerulosclerosis, we first tested whether renal expression levels of carnosine system components correlate with disease. Next, we assessed whether carnosine supplementation in male rats improves pathology. In 10-wk-old phenotypically healthy male and female TGRNeph-hAT1 rats, we compared the renal expression of components of the carnosine system by qRT-PCR. Next, male TGRNeph-hAT1 rats were supplemented with carnosine in drinking water for 20 wk. Subsequently, urinary parameters, renal histology, and renal gene expression of renin-angiotensin system components were assessed. Male TGRNeph-hAT1 rats exhibited less renal expression of carnosine synthase 1, oligopeptide transporter 2, and taurine transporter and higher carnosinase 1 expression than female TGRNeph-hAT1 rats at a young age, before disease starts to develop. Male, but not female, TGRNeph-hAT1 rats developed severe albuminuria, glomerular hypertrophy, and focal and segmental glomerulosclerosis on aging. Carnosine supplementation ameliorated the glomerular hypertrophy but did not affect albuminuria, renal fibrosis, and podocyte loss. Moreover, carnosine significantly reduced renin and increased angiotensin-converting enzyme 2 expression within the kidney. Carnosine treatment alleviates glomerular hypertrophy in TGRNeph-hAT1 rats but does not improve other renal pathologies. Although amelioration of glomerular hypertrophy might be explained by changes in renal renin-angiotensin system expression, further studies are warranted to assess causality. In diabetic kidney disease models, carnosine supplementation ameliorates renal pathology, but its influence in other renal pathologies is less explored. We tested whether renal expression levels of carnosine system components correlate with disease in the model of the transgenic rat TGRNeph-hAT1 with sex-dependent focal segmental glomerulosclerosis and whether carnosine supplementation in male rats improves pathology. Our results provide evidence that carnosine feeding affects the glomerular hypertrophy and renal RAS expression.
CRB2 depletion induces YAP signaling and disrupts mechanosensing in podocytes.
Sun Y, Kronenberg NM, Sethi SK … +10 more , Dash SN, Kovalik ME, Sempowski B, Strickland S, Raina R, Sperati CJ, Tian X, Ishibe S, Hall G, Gather MC
Am J Physiol Renal Physiol · 2025 Apr · PMID 40062402 · Full text
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 c...
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 crumbs homolog-2 (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 two-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 yes-associated protein (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. Although 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. We identified a rare compound heterozygous CRB2 mutation as the cause of familial SRNS/FSGS in a two-generation East Asian kindred. Modeling the effect of the mutation, we show that CRB2 knockdown in podocytes induces YAP transcriptional activity and upregulates YAP-mediated mechanosignaling. Using elastic resonator interference stress microscopy (ERISM), we demonstrate that CRB2 knockdown enhances podocyte contractility in a substrate stiffness-dependent manner. The knockdown effect decreases with increasing substrate stiffness, indicating impaired mechanosensing in CRB2deficient podocytes.
TNF inhibits NKCC2 phosphorylation by a calcineurin-dependent pathway.
Hao S, Lasaracina AP, Epps J … +1 more , Ferreri NR
Am J Physiol Renal Physiol · 2025 Apr · PMID 40062390 · Full text
We previously demonstrated that tumor necrosis factor-alpha (TNF) inhibits Na-K-2Cl cotransporter (NKCC2) phosphorylation in the thick ascending limb (TAL); however, the underlying mechanism remains unclear. We tested th...
We previously demonstrated that tumor necrosis factor-alpha (TNF) inhibits Na-K-2Cl cotransporter (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 twofold 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) α and β isoforms, only CNA β isoform mRNA increased after mTAL cells were challenged with TNF. In vivo, both TNF and CNA β 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 β. Intrarenal injection of a lentivirus that specifically silenced CNA β (U6-CNAβ-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 β isoform, these findings suggest that a CN-dependent signaling pathway involving this isoform contributes to the mechanism by which TNF inhibits pNKCC2 expression. The beneficial immunosuppressive effects of CsA are tempered by renal side effects including reduction of GFR, proximal tubule damage, reduced urinary concentration, fibrosis and hypertension. As chronic administration of CN inhibitors frequently induce hypertension and renal nephropathy in humans, understanding the molecular mechanisms by which CN isoforms regulate the activity of renal transporters may provide the framework for developing new drugs that more selectively modulate the diverse functions of CN.
Effect of sex chromosome complement versus gonadal hormones on abundance of renal transporters.
McDonough AA, Foley TS, Ralph DL … +8 more , Schwindt S, Soong J, Carrisoza-Gaytan R, Lasaad S, Nelson JW, Edwards A, Kleyman TR, Satlin LM
Am J Physiol Renal Physiol · 2025 May · PMID 40062385 · Full text
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...
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 used 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 50 renal transporters and regulators in: FXX gonadal females, FXY gonadal females, MXX Sry males, and MXY XYSry males using semiquantitative 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: sodium/hydrogen exchanger isoform 3 (NHE3), sodium glucose cotransporter 1 (SGLT1), sodium glucose cotransporter 2 (SGLT2), aquaporin 1 (AQP1), medullary alpha1 subunit of sodium-potassium ATPase (mNKAα1), medullary beta1 subunit of sodium-potassium ATPase (mNKAβ1), sodium-chloride cotransporter, and epithelial sodium channel (ENaC) β and -γ subunits. The findings in this FCG model analysis provide the foundation for future studies of the role of sex hormones versus chromosomes on physiologic parameters, including filtration and flow, on transporter covalent modifications, and trafficking in both health and disease. We used the four core genotypes (FCG) mouse model to compare abundance of more than 50 renal transporters and regulators in: FXX gonadal females, FXY gonadal females, MXX Sry males, and MXY XY Sry males using semiquantitative immunoblots. In addition to establishing the significant influence of gonadal hormones, we show, for the first time, that sex chromosome complement (SCC) contributes to sexual dimorphisms in abundance of many renal transporters.
Lysine acetylation of aquaporin-3 promotes water permeability but is not essential for urine concentrating ability.
Huynh NV, Mendoza LD, Nguyen H … +4 more , Rehage C, Saurage EB, Davis P, Hyndman KA
Am J Physiol Renal Physiol · 2025 Apr · PMID 40062363 · Full text
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...
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, or subcellular localization. Urine osmolality of the mutant mice was within the normal range. With dehydration, all mice excreted 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 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. The water channel, AQP3, is lysine 282 acetylated (acAQP3) in rodents and humans. When dehydrated, mouse cortical to inner medullary collecting ducts express acAQP3, suggesting that it promotes water reabsorption. acAQP3 expressing principal cells have high water permeability, and in vivo acute desmopressin resulted in a dilute plasma in female acAQP3 mice. However, all mice produced concentrated urine during water deprivation. Thus, acAQP3 promotes water permeability but is not essential for urine concentration during antidiuresis.
Fueling kidney recovery: boosting BCAA metabolism to overcome nephrotoxic AKI.
Kapitsinou PP
Am J Physiol Renal Physiol · 2025 Apr · PMID 40047271 · Full text
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Nicotinamide ameliorates podocyte injury and albuminuria in adriamycin-induced nephropathy.
Takahashi K, Sato E, Yamakoshi S … +9 more , Ogane M, Sekimoto A, Ishikawa T, Kisu K, Oe Y, Okamoto K, Miyazaki M, Tanaka T, Takahashi N
Am J Physiol Renal Physiol · 2025 Apr · PMID 40033940 · Publisher ↗
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 estab...
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 poly(ADP-ribose) polymerase 1 (PARP-1) was decreased and increased, respectively. Nicotinamide -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. Nephrotic syndrome can lead to end-stage kidney disease and cause severe complications. Currently, effective treatments for nephrotic syndrome have not been established, and new therapeutic approaches targeting podocyte injury are needed. Nicotinamide prevents podocyte injury in adriamycin-induced nephropathy in mice and ameliorates albuminuria, pathological changes, oxidative stress, and inflammation. Here, we provide evidence that pretreatment with nicotinamide can attenuate podocyte injury and subsequent nephropathy in mice.
Proteomic analysis of urinary extracellular vesicles from patients with ADTKD-HNF1β identifies roles for cilia-related proteins and serpins.
Kahlman EJEM, van Heugten MH, Tholen LE … +8 more , Verploegen MFA, Spruijt CG, Jansen PWTC, Vermeulen M, Hoenderop JGJ, Hoorn EJ, Nijenhuis T, de Baaij JHF
Am J Physiol Renal Physiol · 2025 Apr · PMID 40013955 · Publisher ↗
Autosomal dominant tubulointerstitial kidney disease-subtype hepatocyte nuclear factor 1β (ADTKD-HNF1β) is caused by pathogenic variants in or deletions of the gene encoding transcription factor HNF1β. Patients with the...
Autosomal dominant tubulointerstitial kidney disease-subtype hepatocyte nuclear factor 1β (ADTKD-HNF1β) is caused by pathogenic variants in or deletions of the gene encoding transcription factor HNF1β. Patients with the same mutation have variable renal and extrarenal phenotypes, including renal cysts, diabetes, and electrolyte disturbances. The aim of this exploratory study was to provide insight whether pathophysiological effects in the kidney of patients with ADTKD-HNF1β are visible by analyzing their urinary extracellular vesicle (uEV) proteome. We isolated uEVs collected from patients with ADTKD-HNF1β and included patients with autosomal dominant polycystic kidney disease (ADPKD) and patients with chronic kidney disease (CKD) as controls. Subsequent LC-MS/MS proteomics and differential and pathway enrichment analyses were performed. Transcriptional targets of HNF1β were selected with ChIP sequencing to study changes in protein abundance due to loss of HNF1β, and correlation analyses with clinical features were performed. We found differential enrichment of five proteins, enrichment of pathways involved in cilia and cell-cell adhesion, and depletion of several Serpins in patients with ADTKD-HNF1β and ADPKD, compared with patients with CKD. We identified differential enrichment of nine HNF1β transcriptional targets between patients with ADTKD-HNF1β and patients with CKD, and we demonstrated that Serpin abundance negatively correlated with epidermal growth factor receptor (eGFR) in patients with ADTKD-HNF1β ( = -0.52). The uEV proteome of patients with ADTKD-HNF1β shows an enrichment in proteins involved in renal cysts development, with resemblance to ADPKD. These changes provide new insight into the pathophysiology of ADTKD-HNF1β. Their onset and association with cyst development and kidney function decline warrants further study. Urinary extracellular vesicles (uEVs) present a new method to study ADTKD-HNF1β pathophysiology in the kidney as an alternative for kidney biopsies. Enrichment of pathways involved cytoskeletal organization and cilia in the uEV proteome of patients with ADTDK-HNF1β compared with CKD, which may indicate the presence of renal cysts. In this, we show that ADTKD-HNF1β more closely resembles ADPKD. Altogether, the uEV proteome captures the biological changes that are caused by pathogenic variants in HNF1β.
Methylseq, single-nuclei RNAseq, and discovery proteomics identify pathways associated with nephron-deficit CKD in the HSRA rat model.
Milner AR, Johnson AC, Attipoe EM … +3 more , Wu W, Challagundla L, Garrett MR
Am J Physiol Renal Physiol · 2025 Apr · PMID 39982494 · Full text
Low nephron numbers are associated with an increased risk of developing chronic kidney disease (CKD) and hypertension, which are significant global health problems. To investigate the impact of nephron deficiency, our la...
Low nephron numbers are associated with an increased risk of developing chronic kidney disease (CKD) and hypertension, which are significant global health problems. To investigate the impact of nephron deficiency, our laboratory developed a novel inbred rat model (HSRA rat). In this model, ∼75% of offspring are born with a single kidney (HSRA-S), compared with two-kidney littermates (HSRA-C). HSRA-S rats show impaired kidney development, resulting in ∼20% fewer nephrons. Our previous data and current findings demonstrate that nephron deficit (failure of one kidney to form and altered development in the remaining kidney) predisposes HSRA-S to CKD late in life (with increased proteinuria by 18 mo of age in HSRA-S = 51 ± 3.4 vs. HSRA-C = 8 ± 1.5 mg/24 h). To understand early molecular mechanisms contributing to the increased predisposition to CKD, Methylseq using reduced representation bisulfite sequencing, single-nuclei (sn)RNAseq, and discovery proteomics were performed in kidneys of 4-wk-old HSRA rats. Methylation analysis revealed a small number of differences, including five differentially methylated cytosines and six differentially methylated regions between groups. The snRNAseq analysis identified differentially expressed genes in most kidney cell types, with several hundred genes dysregulated depending on the analysis method (Seurat vs. DESeq2). Notably, many genes are involved in kidney development. Discovery proteomic analysis identified 366 differentially expressed proteins. A key finding was dysregulation of /DEPTOR and /AMDHD2 across omics layers, suggesting a potential role in compensatory mechanisms or the genetic basis of altered kidney development. Further understanding of these mechanisms may guide interventions to preserve nephron health and slow kidney disease progression. The HSRA rat is a novel model of nephron deficiency and provides a unique opportunity to study the association between nephron number and chronic kidney disease (CKD). Previous work characterized the impact of age, hypertension, and diabetes on the development of CKD in HSRA animals. This study examined early changes in epigenetics, cell-type specific transcriptome, and proteomic changes in the kidney that likely predispose the model to CKD with age.
HMGB1 drives T-cell activation in hypertensive males and females.
Snyder EC, Mohamed R, Sullivan JC
Am J Physiol Renal Physiol · 2025 Apr · PMID 39982439 · Full text
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...
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. 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.
Endothelial dysfunction in the aging kidney.
Borri M, Jacobs ME, Carmeliet P … +2 more , Rabelink TJ, Dumas SJ
Am J Physiol Renal Physiol · 2025 Apr · PMID 39933752 · Publisher ↗
Global population aging is an escalating challenge in modern society, especially as it impairs the function of multiple organs and increases the burden of age-related diseases. The kidneys, in particular, experience func...
Global population aging is an escalating challenge in modern society, especially as it impairs the function of multiple organs and increases the burden of age-related diseases. The kidneys, in particular, experience function decline, reduced regenerative capacity, and increased susceptibility to injury as they age. As a result, the prevalence of chronic kidney disease (CKD) rises with aging, further contributing to the growing health burden in older populations. One of the key factors in this process is the dysfunction of specialized renal endothelial cells (RECs), which are essential for maintaining kidney health by regulating blood flow and supporting filtration, solute and water reabsorption, and vascular integrity. As the kidneys age, REC dysfunction drives vascular and microenvironmental changes, contributing to the overall decline in kidney function. In this review, we outline the structural and functional effects of aging on the kidney's macrovascular and microvascular compartments and provide a phenotypic description of the aged endothelium. We particularly focus on the molecular and metabolic rewiring driving and sustaining growth-arrested EC senescence phenotype. We finally give an overview of senotherapies acting on ECs, especially of those modulating metabolism. Given that the pathophysiological processes underlying kidney aging largely overlap with those observed in CKD, REC rejuvenation could also benefit patients with CKD. Moreover, such interventions may hold promise in improving the outcomes of aged kidney transplants. Hence, advancing our understanding of REC and kidney aging will create opportunities for innovations that could improve outcomes for both elderly individuals and patients with CKD.
Sphingolipid signaling in kidney diseases.
Li N, Li G
Am J Physiol Renal Physiol · 2025 Mar · PMID 39933715 · Full text
Sphingolipids are a family of bioactive lipids. The key components include ceramides, ceramide-1-phosphate, sphingosine, and sphingosine-1-phosphate. Sphingolipids were originally considered to be primarily structural el...
Sphingolipids are a family of bioactive lipids. The key components include ceramides, ceramide-1-phosphate, sphingosine, and sphingosine-1-phosphate. Sphingolipids were originally considered to be primarily structural elements of cell membranes but were later recognized as bioactive signaling molecules that play diverse roles in cellular behaviors such as cell differentiation, migration, proliferation, and death. Studies have demonstrated changes in key components of sphingolipids in the kidneys under different conditions and their important roles in the renal function and the pathogenesis of various kidney diseases. This review summarizes the most recent advances in the role of sphingolipid signaling in kidney diseases.
Looking below the surface: using intravital imaging to decipher inflammatory renal disease and renal cell injury.
Hickey MJ, Sudhakar V
Am J Physiol Renal Physiol · 2025 Mar · PMID 39918796 · Publisher ↗
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...
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.
Renal macro- and microcirculatory perturbations in acute kidney injury and chronic kidney disease associated with heart failure and cardiac surgery.
Trask-Marino AL, Marino B, Lancefield TF … +5 more , See EJ, May CN, Booth LC, Raman J, Lankadeva YR
Am J Physiol Renal Physiol · 2025 Apr · PMID 39918776 · Publisher ↗
Chronic kidney disease (CKD) affects 50% of patients with heart failure. The pathophysiology of CKD in heart failure is proposed to be driven by macrocirculatory hemodynamic changes, including reduced cardiac output and...
Chronic kidney disease (CKD) affects 50% of patients with heart failure. The pathophysiology of CKD in heart failure is proposed to be driven by macrocirculatory hemodynamic changes, including reduced cardiac output and elevated central venous pressure. However, our understanding of renal microcirculation in heart failure and CKD remains limited. This is largely due to the lack of noninvasive techniques to assess renal microcirculation in patients. Moreover, there is a lack of clinically relevant animal models of heart failure and CKD to advance our understanding of the timing and magnitude of renal microcirculatory dysfunction. Patients with heart failure and CKD commonly require cardiac surgery with cardiopulmonary bypass (CPB) to improve their prognosis. However, acute kidney injury (AKI) is a frequent unresolved clinical complication in these patients. There is emerging evidence that renal microcirculatory dysfunction, characterized by renal medullary hypoperfusion and hypoxia, plays a critical role in the pathogenesis of cardiac surgery-associated AKI. In this review, we consolidate the preclinical and clinical evidence of renal macro- and microcirculatory perturbations in heart failure and cardiac surgery requiring CPB. We also examine emerging biomarkers and therapies that may improve health outcomes for this vulnerable patient population by targeting the renal microcirculation.
The impact of maternal obesity on polycystic kidney disease progression in a mouse model.
Miller SJ, Hill K, Darby I … +4 more , Nusrat F, Friedman JE, Rudolph MC, Zimmerman KA
Am J Physiol Renal Physiol · 2025 Mar · PMID 39908005 · Full text
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...
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 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. 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 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.
Integration of metabolomics and transcriptomics reveals the mechanism of TMEM30A downregulation induced FSGS podocyte injury.
Hou Y, Chen S, Li Y … +9 more , Huang L, Zhang H, Yu M, Xiong L, Zhong X, Wang L, Zhu X, Li G, Peng L
Am J Physiol Renal Physiol · 2025 Mar · PMID 39907744 · Publisher ↗
Podocyte injury plays a critical role in the pathogenesis and progression of focal and segmental glomerulosclerosis (FSGS). Transmembrane protein 30 A (TMEM30A) downregulation participates in podocyte injury. This study...
Podocyte injury plays a critical role in the pathogenesis and progression of focal and segmental glomerulosclerosis (FSGS). Transmembrane protein 30 A (TMEM30A) downregulation participates in podocyte injury. This study aimed to identify the critical pathways and molecules associated with the downregulation of TMEM30A in the context of FSGS podocyte injury. In our study, we found that TMEM30A and podocyte marker Synaptopodin were significantly downregulated in kidney tissues from patients with FSGS compared with those in normal controls. Using transcriptomic and metabolomic analyses, we characterized knockdown (KD) and normal mouse podocytes to identify differentially expressed genes and metabolites. Then, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and Protein-Protein Interaction (PPI) network were constructed, and the differentially expressed genes and metabolites were enriched into glycolytic pathway. Furthermore, we found that the key glycolytic enzymes were downregulated in patients with FSGS, podocyte-specific ; mice, and KD mouse podocytes. For rescue experiments, shTmem30a-resistant cDNA (resTmem30a) was created to intervene KD mouse podocytes. And we observed that podocyte-related molecules were downregulated in the KD group, along with glycolysis-related molecules, but the resTmem30a partially reversed this trend. Our findings clarified that TMEM30A downregulation initiates podocyte injury by reducing glycolysis-related molecules (ALDOA, HK2, LDHA, and GAPDH) in FSGS and has implications for early diagnosis, prevention, and treatment. This study aimed to identify the key pathways and molecules of TMEM30A downregulation involved in FSGS podocyte injury. Through comprehensive transcriptomic and metabolomic analyses, as well as in vivo and in vitro experiments, we discovered that the downregulation of TMEM30A triggers podocyte injury by decreasing the levels of glycolysis-related molecules, including ALDOA, HK2, LDHA, and GAPDH, in FSGS.
ERMP1 as a newly identified endoplasmic reticulum stress gatekeeper in chronic kidney disease.
Correia de Sousa M, Arnoux G, Yvon R … +13 more , Maeder C, Fournier M, Morin N, Dolicka D, Delangre E, Türkal M, Charlemagne T, de Seigneux S, Legouis D, Maechler P, Feraille E, Foti M, Gjorgjieva M
Am J Physiol Renal Physiol · 2025 Mar · PMID 39873175 · Publisher ↗
Endoplasmic reticulum metallopeptidase 1 (ERMP1) is involved in the unfolded protein response (UPR) pathway in response to the endoplasmic reticulum (ER) stress. Given the pivotal role of ER stress in the pathogenesis of...
Endoplasmic reticulum metallopeptidase 1 (ERMP1) is involved in the unfolded protein response (UPR) pathway in response to the endoplasmic reticulum (ER) stress. Given the pivotal role of ER stress in the pathogenesis of acute and chronic kidney diseases, we hypothesized that ERMP1 could be instrumental in the development of renal injury. In silico analysis of RNA sequencing datasets from renal biopsies were exploited to assess the expression of ERMP1 in the kidney under normal or pathological conditions. CRISPR-Cas9-mediated heterozygous genetic ablation of the exon 1 of was performed in vivo, followed by histological analysis and assessment of renal injury and ER stress markers in the newly generated knockout mouse model. In addition, knockdown and overexpression of ERMP1 were conducted in human tubular cells to investigate cell viability, metabolism, the UPR pathway, and ER Ca release under these conditions. Our findings from patient datasets showed that ERMP1 is expressed in all renal cell types and is upregulated in chronic kidney disease. Further in silico investigations suggest a role for ERMP1 in renal development. ERMP1 knockout in mice revealed that homozygous loss of ERMP1 expression is lethal, whereas heterozygous loss exacerbated age-related chronic kidney alteration. In human tubular cells, ERMP1 knockdown decreased viability and metabolic rate, whereas overexpression conferred protection against ER stress. These results highlight the importance of ERMP1 in renal physiology and pathology and suggest that its upregulation could be a protective mechanism against excessive ER stress in renal tubule epithelial cells. Our study reveals an increase in ERMP1 expression in acute and chronic kidney diseases, potentially serving as a protective mechanism against excessive ER stress. Conversely, a decline in ERMP1 expression in the kidney exacerbates age-related chronic kidney disease. Overall, the study enhances our understanding of the role of ERMP1 in kidney pathophysiology, paving the way for future research and therapeutic developments aimed at improving outcomes for patients with kidney diseases.
Furin-mediated modification is required for epithelial sodium channel-activating activity of soluble (pro)renin receptor in cultured collecting duct cells.
Zheng H, Helms MN, Zou C … +3 more , Zimmerman E, Feng Y, Yang T
Am J Physiol Renal Physiol · 2025 Jun · PMID 39871593 · Publisher ↗
(Pro)renin receptor (PRR) contains an overlapping cleavage site for site-1 protease (S1P) and furin for the generation of soluble PRR (sPRR). Although S1P-mediated cleavage mediates the release of sPRR, the functional im...
(Pro)renin receptor (PRR) contains an overlapping cleavage site for site-1 protease (S1P) and furin for the generation of soluble PRR (sPRR). Although S1P-mediated cleavage mediates the release of sPRR, the functional implication of furin-mediated cleavage is unclear. Here, we tested whether furin-mediated cleavage was required for the activity of sPRR in activating epithelial Na channel (ENaC) in cultured M-1 cells. M-1 cells were transfected with pcDNA3.4 containing full-length PRR with (Furin-site Mut) or without (WT) mutagenesis of the furin cleavage site. As compared with empty vector (EM) control, Furin-site Mut showed the attenuation effect on WT-induced α-ENaC expression and amiloride-sensitive short-circuit current. In a separate experiment, M-1 cells were transfected with pcDNA3.4 containing cDNA for sPRR with S1P cleavage (AA 1-282) (sPRR-S1P) or with furin cleavage (AA 1-279) (sPRR-furin), indicating overexpression of the two types of sPRR induced a significant and comparable increase in the release of sPRR, but only sPRR-furin showed an increase of ENaC activity. Single-channel analysis of ENaC activity in Xenopus A6-2F3 cells confirms sPRR-furin activation of ENaC open probability. At last, HEK-293 cells were pretreated with furin inhibitor α-antitrypsin Portland (α-PDX) followed by transfection with EM, WT PRR. sPRR in the conditioned medium was enriched by using protein centrifugal filter devices and applied to M-1 cells followed by measurement of ENaC activity, demonstrating that pretreatment with α-PDX attenuated ENaC-acting activity induced by overexpression of WT PRR. In summary, we conclude that furin-mediated modification is required for the activity of sPRR to increase ENaC-mediated Na transport in the collecting duct cells. The present study for the first time examined the functional implication of furin-dependent cleavage in the activation of sPRR during ENaC regulation in cultured CD cells. We found that sPRR with the initial S1P-dependent cleavage remained silent and only became active following furin-dependent cleavage in terms of enhancement of ENaC activity and expression of α-ENaC. These results offer novel insight into the sPRR maturation process during ENaC regulation.
Recent advances on immunity and hypertension: the new cells on the kidney block.
Dasinger JH, Abais-Battad JM, McCrorey MK … +1 more , Van Beusecum JP
Am J Physiol Renal Physiol · 2025 Mar · PMID 39853324 · Full text
Over the past 50 years, the contribution of the immune system has been identified in the development of hypertension and renal injury. Both human and experimental animal models of hypertension have demonstrated that inna...
Over the past 50 years, the contribution of the immune system has been identified in the development of hypertension and renal injury. Both human and experimental animal models of hypertension have demonstrated that innate and adaptive immune cells, along with their cytokines and chemokines, modulate blood pressure fluctuations and end organ renal damage. Numerous cell types of the innate immune system, specifically monocytes, macrophages, and dendritic cells, present antigenic peptides to T cells, promoting inflammation and the elevation of blood pressure. These T cells and other adaptive immune cells migrate to vascular and tubular cells of the kidney and promote end-organ fibrosis, damage, and ultimately hypertensive injury. Through the development of high-throughput screening, novel renal and immune cell subsets have been identified as possible contributors and regulators of renal injury and hypertension. In this review, we will consider classical immunological cells and their contribution to renal inflammation, and novel cell subsets, including renal stromal cells, that could potentially shed new light on renal injury and hypertension. Finally, we will discuss how interorgan inflammation contributes to the development of hypertension and hypertension-related multiorgan damage, and explore the clinical implications of the immunological components of renal injury and hypertension.
Ribosomal s6 kinase is a mediator of aquaporin-2 S256 phosphorylation and membrane accumulation after EGFR inhibition with erlotinib.
Babicz RSE, Baylor N, Terlouw A … +5 more , Faber DA, Fukushima K, Biondi RM, Bouley R, Brown D
Am J Physiol Renal Physiol · 2025 Mar · PMID 39823198 · Full text
Vasopressin (VP) activates protein kinase A (PKA), resulting in phosphorylation events and membrane accumulation of aquaporin-2 (AQP2). Epidermal growth factor receptor (EGFR) inhibition with erlotinib also induces AQP2...
Vasopressin (VP) activates protein kinase A (PKA), resulting in phosphorylation events and membrane accumulation of aquaporin-2 (AQP2). Epidermal growth factor receptor (EGFR) inhibition with erlotinib also induces AQP2 membrane trafficking with a phosphorylation pattern similar to VP, but without increasing PKA activity. Here, we identify the ribosomal s6 kinase (RSK) as a major mediator phosphorylating AQP2 in this novel, erlotinib-induced pathway. We found that RSK was expressed in collecting duct principal cells in rat kidneys. RSK inhibition with BI-D1870 blocked erlotinib-induced AQP2 serine 256 (S256) phosphorylation and membrane accumulation. CRISPR-generated RSK knockout (KO) cells failed to show increased S256 phosphorylation in response to erlotinib. Like PKA, RSK was able to phosphorylate AQP2 S256 in vitro. Inhibition of phosphoinositide-dependent kinase-1 (PDK1), a known activator of RSK, blocked erlotinib-induced AQP2 S256 phosphorylation and membrane accumulation. We conclude that RSK is a crucial terminal kinase phosphorylating AQP2 at S256 upon EGFR inhibition by erlotinib. Epidermal growth factor receptor (EGFR) inhibition with erlotinib induces aquaporin-2 (AQP2) membrane accumulation with a phosphorylation pattern similar to vasopressin (VP). Here, we identify the ribosomal s6 kinase (RSK) as a major mediator phosphorylating AQP2 in this novel, erlotinib-induced pathway. In addition, we show that phosphoinositide-dependent kinase-1 (PDK1), a known activator of RSK, is implicated in this pathway: PDK1 inhibition blocks erlotinib-induced AQP2 S256 phosphorylation and membrane accumulation.
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