Nephrology
Abstract
Obesity is a major risk factor for chronic kidney disease. Time-restricted feeding (TRF) shows promise to reduce kidney inflammation in chronic kidney disease. We hypothesized that TRF blunts kidney fibrosis in obese mice by mitigating T cell inflammation. We used a diet-induced obese mouse model fed a high fat diet (DIO, 45% fat) ad libitum for 18 weeks followed by 2 weeks of TRF or ad libitum high fat feeding. We found that TRF reversed kidney fibrosis as well as reduced kidney CD8+ T cells in DIO mice. Our study also revealed that DIO mice had increased kidney CD8+ T cell infiltration from the small intestine that was blunted with TRF. Furthermore, anti-CD8 intervention in DIO showed reduced kidney fibrosis and damage compared to anti-IgG treated DIO mice. Single cell RNA sequencing data revealed that DIO increased, while TRF reduced, the frequency of a specific cluster of CD8+ T cells that featured high expression of exhaustion/activation genes. Spatial analyses showed DIO mice had significant infiltration of PD-1+CD8+ T cells near CD31+ endothelial cells that was diminished by TRF. In conclusion, this study discovered that TRF reverses kidney fibrosis through reducing CD8+ T cell infiltration in obese mice.
Authors
Claudia J. Edell, John D. Erickson, Xiaofen Liu, Savannah C. Walker, Jackson Colson, Michael Heim, Pranav Nagila, Kyle H. Moore, Keri M. Kemp, Kelly Hyndman, Selene Meza-Perez, Troy D. Randall, Annye P. Bennett, Anna G. Sorace, Yu-Hua Dean Fang, David M. Pollock, Carmen De Miguel, Julienne L. Carstens, Jennifer S. Pollock
Abstract
The pathogenesis of Bartter syndrome (BS) has long been attributed to decreased salt reabsorption in the thick ascending limb of Henle’s loop (TAL). By studying Clc-k2 (mouse ortholog of ClC-Kb)-knockout (Clc-k2-/-) mice, we recently uncovered an additional mechanism in which loss of Clc-k2 induces TAL hypoplasia in neonatal kidneys, exacerbating BS severity. Here, we further investigated this mechanism. TALs and distal convoluted tubules (DCTs) isolated from Clc-k2-/- and wild-type mice were used for transcriptome, proteomics, cell cycle, and proliferation assays. Mitochondrial morphology and function were studied using electron microscopy and mitochondrial respiration assays. Our results revealed impairments in cell proliferation, S-to-G2/M cell cycle transition, mitochondrial biogenesis, oxidative phosphorylation, glycolysis, and fatty acid oxidation in Clc-k2-/- TALs and DCTs. Increasing transport function by introducing a gain-of-function with-no-lysine kinase 4 mutation in Clc-k2-/- mice restored these metabolic and proliferative impairments and improved phenotype. Transgenic expression of peroxisome proliferator-activated receptor gamma coactivator-1α, a master regulator of mitochondrial biogenesis, in Clc-k2-/- mice also alleviated mitochondrial dysfunction and phenotype. These findings support the hypothesis that mitochondrial hypofunction, resulting from decreased transport function, contributes to cell cycle arrest and tubular hypoplasia in BS. Targeting mitochondria early in life could be a potential therapeutic approach for BS.
Authors
Chiao-Hui Hsieh, Yu-Jen Chen, Chih-Chien Sung, Emily Morrison, Chou-Long Huang, Chih-Jen Cheng
Abstract
Systemic lupus erythematosus (SLE) is a progressive autoimmune disease that affects multiple organs and tissues, with lupus nephritis (LN) as one of its most severe complications. While LN progression is associated with compromised permeability of human renal glomerular endothelial cells (HRGECs), the underlying mechanisms are not fully defined. Herein, we demonstrate that aberrant glycolysis drives this glomerular endothelial barrier defect by suppressing the transcription of tight junction (TJ) genes. Mechanistically, circulating self-DNA in SLE plasma acts as a ligand that activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in HRGECs, driving aberrant glycolytic adaption. The resulting glycolytic product, lactate, serves as a substrate for protein lactylation, leading to extensive lactylation and subsequent ubiquitination of the enhancer of zeste homolog 2 (EZH2). In consequence, EZH2 deficiency results in reduced H3K27me3 levels, thereby suppressing the transcription of TJ genes. In a self-DNA-induced SLE model, inhibition of cGAS-STING signaling or lactate production effectively restored the integrity of TJs of HRGECs and concurrently alleviated key LN symptoms. Together, lactate programs lactylation and ubiquitination of EZH2 to impair glomerular endothelial barrier in human SLE.
Authors
Jiaxin Lei, Xingyu Zhai, Yixin Wang, Ying Li, Lei Li, Mengdi Liu, Jing Guo, Lingyi Li, Zhezhuyun Chen, Qinghua Cao, Zhichun Liu, Ting Liu, Lin Xu, Zhenke Wen
Abstract
Chronic kidney disease is a global health concern characterized by maladaptive repair processes leading to kidney fibrosis. Following injury, early alterations in the extracellular matrix precede the development of kidney fibrosis and represent potential therapeutic targets to improve kidney repair. In this context, studies from our laboratory and others have shown that the matricellular protein SMOC2 can be targeted to decrease inflammation and tubulointerstitial fibrosis following kidney injury. The tubular epithelial cells (TECs), which are abundant and particularly susceptible to injury, play a central role in maladaptive repair; however, whether SMOC2 affects their functionality after kidney injury has not been explored. In this study, we show that SMOC2 localizes to the basement membrane of injured TECs across three murine models of kidney injury. Our in vitro studies demonstrate that SMOC2 induces a partial epithelial-to-mesenchymal (EMT) transition of TECs. We further demonstrate that its extracellular calcium-binding domain mediates binding to the decellularized extracellular matrix and mediates most of its effects on TECs. Mechanistically, SMOC2 promotes partial EMT effects through an integrin-dependent pathway. Together, these findings provide new mechanistic insight into how SMOC2 drives maladaptive repair by modulating TEC behavior and identify its calcium-binding domain as a key functional mediator.
Authors
Schrodinger Cenatus, Peng Gao, Nathalie Henley, Caroline Lamarche, Xue-Song Liu, Frédérick A. Mallette, Jonatan Barrera-Chimal, Casimiro Gerarduzzi
Abstract
BACKGROUND Acute interstitial nephritis (AIN) is a common cause of acute kidney injury (AKI), but the diagnosis may be missed as kidney biopsies are rarely obtained when acute tubular injury (ATI) is suspected.METHODS The Kidney Precision Medicine Project is a cohort study that obtains kidney biopsies from individuals with AKI, which undergo pathologic and molecular interrogation. We compared ATI and AIN cases among the first 60 AKI participants.RESULTS On clinicopathologic adjudication, 30 patients (50%) had a primary adjudicated diagnosis of ATI, 13 (22%) patients had AIN, 9 (15%) had diabetic nephropathy, and 3 (5%) had other conditions. There were increased interstitial white blood cells and tubulitis (P < 0.05 for both) in AIN compared with ATI. Prior to biopsy, the treating clinician suspected ATI in 83% of the cases with adjudicated ATI, while the treating clinician suspected AIN in 54% of the cases with AIN. Tissue transcriptomic signatures showed enrichment of proinflammatory signaling and increased expression of CXCL9, a chemokine induced by IFN-γ, in myeloid cells of participants with AIN. CXCL9 localized to inflammatory infiltration in spatial transcriptomic data.CONCLUSION Adjudication of kidney biopsies revealed distinct pathologic and molecular profiles between ATI and AIN. Kidney biopsy should be considered more frequently in AKI, as AIN is clinically underrecognized.TRIAL REGISTRATION ClinicalTrials.gov NCT04334707.FUNDING National Institute of Diabetes and Digestive and Kidney Diseases grants U01DK133081, U01DK133091, U01DK133092, U01DK133093, U01DK133095, U01DK133097, U01DK114866, U01DK114908, U01DK133090, U01DK133113, U01DK133766, U01DK133768, U01DK114907, U01DK114920, U01DK114923, U01DK114933, U24DK114886, UH3DK114926, UH3DK114861, UH3DK114915, and UH3DK114937.
Authors
Jennifer A. Schaub, Rajasree Menon, Ricardo Melo Ferreira, Elizabeth Kiernan, Insa M. Schmidt, Christine P. Limonte, Soumya Yennapureddy, Ying-Hua Cheng, Leal Herlitz, Avi Z. Rosenberg, Joel M. Henderson, Kelly D. Smith, Jeffrey B. Hodgin, Edgar Otto, Gilbert W. Moeckel, Lloyd G. Cantley, Suman Setty, Ulysses G.J. Balis, Dawit Demeke, Agnes B. Fogo, Andrew S. Bomback, Vivette D. D’Agati, Isaac E. Stillman, Jose R. Torrealba, Allen R. Hendricks, Erika Bracamonte, Vanessa Moreno, Pavan Bhatraju, Amy K. Mottl, Frank C. Brosius, Bijin Thajudeen, Steven G. Coca, Paul M. Palevsky, Parmjeet S. Randhawa, Raghavan Murugan, Laura Barisoni, Charles E. Alpers, Steven Menez, F. Perry Wilson, Dennis G. Moledina, Michael T. Eadon, Matthias Kretzler, Jonathan Himmelfarb, Chirag R. Parikh, the Kidney Precision Medicine Project
Abstract
Obstructive nephropathy is a significant and preventable contributor to chronic kidney disease, yet no disease-modifying anti-fibrotic agents are currently available.We hypothesized that interferon regulatory factor 5 (IRF5) functions as a macrophage transcriptional regulator that directly transactivates matrix metalloproteinase 9 (MMP9) to initiate early extracellular matrix (ECM) remodeling. Analysis of 30 human obstructive nephropathy biopsy specimens demonstrated that IRF5+CD68+ macrophage density increased progressively with fibrosis severity and correlated significantly with α-smooth muscle actin (α-SMA) positive areas. In the murine unilateral ureteral obstruction (UUO) model, both global and myeloid-specific Irf5 deletion significantly attenuated collagen deposition, immune cell infiltration, and fibrotic gene expression compared with wild-type controls. Cleavage under targets and tagmentation (CUT&Tag) analysis demonstrated that IRF5 directly binds the Mmp9 enhancer region and increases chromatin accessibility. Consequently, myeloid-specific Irf5 knockout significantly reduced Mmp9 mRNA and MMP9 protein levels. Pharmacological inhibition using the IRF5 inhibitor N5-1 mitigated established fibrosis, down-regulated α-SMA and MMP9 expression, and reduced CD68+ macrophage infiltration. These findings identify the IRF5-MMP9 axis as a therapeutically targetable pathway driving macrophage-mediated ECM expansion and provide pre-clinical evidence supporting IRF5 inhibition as a potential treatment strategy for patients with obstructive nephropathy.
Authors
Jia Wei, Gengyu Du, Zixia Li, Min Yang, Ting Chen, Zihao Xu, Zhen Yuan, Yidan Zheng, Xiang Yan
Abstract
Polycystic kidney disease (PKD) arises from mutations in cilia-associated genes, such as PKD1 and PKD2, expressed in renal epithelial cells, leading to progressive kidney dysfunction and end-stage kidney disease (ESKD). PKD patients exhibit significant heterogeneity in disease progression, largely due to genetic and environmental modifiers. Like patients, mouse models of PKD also exhibit significant heterogeneity with regards to the gene mutated, age of disease onset, and rate of disease progression. To elucidate the cellular and molecular consequences of these variables, we constructed an integrated single-cell RNA sequencing atlas across mouse models of PKD, mapping changes in cell type composition, gene expression, and intercellular signaling networks across the whole atlas and within individual models. Across models, single cell RNA sequencing (scRNAseq) data revealed increased Spp1 (osteopontin) expression and signaling from PKD-enriched clusters. Global deletion of Spp1 in Pkd1RC/RC mice resulted in a modest reduction in cyst severity and improved kidney function. From these studies, we created a freely available, searchable website (https://bmblx.bmi.osumc.edu/scPKD/) that can be used to identify cross- and intra-model changes in gene expression, guiding researchers to new therapeutic targets for treating PKD.
Authors
Sarah J. Miller, Hua Zhong, Weidong Wu, Audrey M. Cordova, Morgan E. Yashchenko, Alex Yashchenko, Zhang Li, Daniyal J. Jafree, Chelsea N. Zimmerman, Christa I. DeVette, Vicki Do, Maya E. Hignite, Yohan Park, Fariha Nusrat, Bibi Maryam, Sizhao Lu, Xiaoyan Li, Jenny R. Gipson, Xiaogang Li, David A. Long, Mary C.M. Weiser-Evans, Bradley K. Yoder, Benjamin D. Cowley, Jr., Katharina Hopp, Jason R. Stubbs, Qin Ma, Anjun Ma, Kurt A. Zimmerman
Abstract
Renin cells are essential for survival and serve as key regulators of blood pressure and fluid-electrolyte homeostasis. Their function and identity are dependent on signals from their local microenvironment afforded by neighboring cells and nerves. Whether and how renin cells contribute to the development and maintenance of this microenvironment remains unclear. Because renin cells are rare -0.01 % of kidney cells- conventional histological approaches cannot capture their interaction with nerve fibers and surrounding cells within the nephron and its vasculature. Using high-resolution 3D imaging, cell-specific multicolor reporter mice, single-cell RNA-Seq, and conditional gene deletions, we mapped how renin cells assemble within arterioles and communicate with axon fibers to organize the growth and orientation of the kidney arterioles during development and disease. This co-inductive process is mediated by Ngf produced by renin cell precursors and is necessary for renin cell survival and innervation. Interestingly, renin enzymatic insufficiency elevates Ngf and drives arteriolar hypertrophy with aberrant axon sprouting and hyperinnervation. These findings indicate that renin cells regulate kidney neurovascular development revealing them as active organizers of their local neuroregulatory microenvironment in health and disease.
Authors
Manako Yamaguchi, Georgina Gyarmati, Liam McLaughlin, Hiroki Yamaguchi, Jason P. Smith, Lucas Ferreira de Almeida, Daisuke Matsuoka, Alexandre G. Martini, Sara M. Wilmsen, Sijie Hao, Kazuki Tainaka, Silvia Medrano, Sanjay Jain, Janos Peti-Peterdi, Maria Luisa S. Sequeira-Lopez, R. Ariel Gomez
Abstract
Authors
Muhammad Atif Rauf, Sanskriti Agarwal, Rebecca R. Baker, Jennifer Steeden, Alfredo Petrosino, Maria Kiliaris, Robert Unwin, Keith Siew, Alan D. Salama, Rhys D.R. Evans
Abstract
BACKGROUND. Primary laminopathies are a heterogeneous group of rare diseases caused by nuclear lamina dysfunction due to pathogenic LMNA variants. However, despite their ubiquitous expression, LMNA variants have rarely been linked to chronic kidney disease (CKD). Here, we systematically investigate clinical implications and functional underpinnings of a distinct LMNA missense variant (lamin A/C p.(Arg349Trp)) that has sporadically been found in patients with a complex phenotype including lipodystrophy, proteinuria, and focal segmental glomerulosclerosis (FSGS). METHODS. In clinical and functional terms, we compare lamin A/C Arg349Trp with missense changes at Arg482, the most common hotspot residue for type 2 familial partial lipodystrophy (FPLD2). In particular, we assess renal endpoints in corresponding patient cohorts and investigate disease-associated alterations in vitro. RESULTS. In contrast to FPLD2 patients, individuals with lamin A/C Arg349Trp experience high-grade proteinuria and a rapid decline of glomerular filtration rate with kidney failure at a median age of 43 years. Mechanistically, we demonstrate that Arg349Trp associates with an abrogation of the structural interaction between lamin A/C and nucleoporin 155, nuclear pore complex aggregation, and an alteration of TGF-β1-dependent signaling. CONCLUSIONS. While patients with Lamin A/C Arg482 missense changes are at very low risk for progressive CKD, patients harboring Arg349Trp show nephrotic range proteinuria and kidney failure in midlife. Hence, high-grade proteinuric kidney disease is genotype-specific and patients with the Arg349Trp substitution require early renoprotective intervention to potentially halt progression and prevent kidney failure. FUNDING. German Research Foundation, project IDs 502928386, 445703531, and grants HA 9779/2-1, HA 6908/4-1, HA 6908/7-1, HA 6908/8-1, HA 6908/12-1.
Authors
Sebastian Sewerin, Charlotte Aurnhammer, Mohamed Hamed, Gwladys Revêchon, Ria Schönauer, Christin Findeisen, Konstanze Miehle, Šárka Tesařová, Theodoros Georgomanolis, Carsten Bergmann, Constantin A. Wolff, Marek Kollár, Baris Akinci, David Araujo-Vilar, Giovanni Ceccarini, Éva Csajbók, Alessandra Gambineri, Martin Heni, Thomas Scherer, Iztok Štotl, Ekaterina Sorkina, Marie-Christine Vantyghem, Elena Vorona, Martin Wabitsch, Julia von Schnurbein, Camille Vatier, Joëlle Roume, Yves Reznik, Maria Eriksson, Wolfram Antonin, Corinne Vigouroux, Jan Halbritter
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