Kidney repair and regeneration: perspectives of the NIDDK (Re)Building a Kidney consortium
Authors: Bilal A. Naved, Joseph V. Bonventre, Jeffrey A. Hubbell, Neil A. Hukriede, Benjamin D. Humphreys, Carl Kesselman, M. Todd Valerius, Andrew P. McMahon, Stuart J. Shankland, Jason A. Wertheim, Michael J.V. White, Mark P. de Caestecker, Iain A. Drummond
Journal: Kidney International (2022)

Acute kidney injury impacts ∼13.3 million individuals and causes ∼1.7 million deaths per year globally. Numerous injury pathways contribute to acute kidney injury, including cell cycle arrest, senescence, inflammation, mitochondrial dysfunction, and endothelial injury and dysfunction, and can lead to chronic inflammation and fibrosis. However, factors enabling productive repair versus nonproductive, persistent injury states remain less understood. The (Re)Building a Kidney (RBK) consortium is a National Institute of Diabetes and Digestive and Kidney Diseases consortium focused on both endogenous kidney repair mechanisms and the generation of new kidney tissue. This short review provides an update on RBK studies of endogenous nephron repair, addressing the following questions: (i) What is productive nephron repair? (ii) What are the cellular sources and drivers of repair? and (iii) How do RBK studies promote development of therapeutics? Also, we provide a guide to RBK's open access data hub for accessing, downloading, and further analyzing data sets. Acute kidney injury impacts ∼13.3 million individuals and causes ∼1.7 million deaths per year globally. Numerous injury pathways contribute to acute kidney injury, including cell cycle arrest, senescence, inflammation, mitochondrial dysfunction, and endothelial injury and dysfunction, and can lead to chronic inflammation and fibrosis. However, factors enabling productive repair versus nonproductive, persistent injury states remain less understood. The (Re)Building a Kidney (RBK) consortium is a National Institute of Diabetes and Digestive and Kidney Diseases consortium focused on both endogenous kidney repair mechanisms and the generation of new kidney tissue. This short review provides an update on RBK studies of endogenous nephron repair, addressing the following questions: (i) What is productive nephron repair? (ii) What are the cellular sources and drivers of repair? and (iii) How do RBK studies promote development of therapeutics? Also, we provide a guide to RBK's open access data hub for accessing, downloading, and further analyzing data sets. Despite advances in kidney care and efforts to delay development of chronic kidney disease (CKD), acute kidney injury (AKI) and progression to CKD remains a major health care burden.1Mehta R.L. Cerdá J. Burdmann E.A. et al.International Society of Nephrology's 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology.Lancet. 2015; 385: 2616-2643Google Scholar The (Re)Building a Kidney consortium (RBK) is a National Institute of Diabetes and Digestive and Kidney Diseases consortium tasked with finding ways to improve kidney repair and forestalling progression to CKD, as well as devising innovative approaches to generation and engraftment of kidney replacement tissue.2The RBK consortiumThe NIDDK rebuilding a kidney consortium.https://www.rebuildingakidney.orgDate accessed: December 1, 2021Google Scholar Forestalling progression of CKD requires an understanding of endogenous kidney repair mechanisms and discriminating between productive repair and nonproductive, profibrotic conditions. Mouse models show that nephron tubules have an intrinsic regenerative potential3Kusaba T. Lalli M. Kramann R. et al.Differentiated kidney epithelial cells repair injured proximal tubule.Proc Natl Acad Sci U S A. 2014; 111: 1527-1532Google Scholar; however, on repeated injury, cells can be diverted to a nonproductive senescent state. RBK research groups focus on ischemia-reperfusion injury (IRI) to induce AKI because it is the most common cause of AKI and, as an experimental model in mice, can be performed with variable ischemic durations to produce mild or severe tubule injury and model the AKI-to-CKD progression. Whole kidney RNA-sequencing characterization after murine ischemia-reperfusion following recovery from IRI for 12 months provided clues about repair processes and the AKI-CKD transition4Liu J. Kumar S. Dolzhenko E. et al.Molecular characterization of the transition from acute to chronic kidney injury following ischemia/reperfusion.JCI Insight. 2017; 2e94716Google Scholar (Figure 1).5Gerhardt L.M.S. Liu J. Koppitch K. et al.Single-nuclear transcriptomics reveals diversity of proximal tubule cell states in a dynamic response to acute kidney injury.Proc Natl Acad Sci U S A. 2021; 118e2026684118Google Scholar, 6Kirita Y. Wu H. Uchimura K. et al.Cell profiling of mouse acute kidney injury reveals conserved cellular responses to injury.Proc Natl Acad Sci U S A. 2020; 117: 15874-15883Google Scholar, 7Dixon E. Wu H. Muto Y. et al.Spatially resolved transcriptomic analysis of acute kidney injury in a female murine model.J Am Soc Nephrol. 2022; 33: 279-289Google Scholar Principle component analysis uncovered a cascade of gene expression patterns that mapped to tubular injury/repair, fibrosis, and innate and adaptive immunity processes. Specific genes, like Krt20, a kidney injury marker, tracked progressive proximal tubular injury, whereas genes related to cell cycle and wound repair were transiently upregulated after IRI. Sox9, a transcription factor linked to proximal tubular repair and unresolved injury, remained persistently upregulated over the course of recovery. This study highlighted coregulated gene clusters associated with the progression of AKI to CKD and revealed that the AKI-CKD transition can occur after a single ischemic episode.4Liu J. Kumar S. Dolzhenko E. et al.Molecular characterization of the transition from acute to chronic kidney injury following ischemia/reperfusion.JCI Insight. 2017; 2e94716Google Scholar In subsequent studies, single-nucleus RNA sequencing identified distinct, late-stage injury, proximal tubule cell states (Vcam1+ /Ccl2+ with upregulation of nuclear factor-κB, tumor necrosis factor, and AP-1 signaling pathways) associated with the AKI-CKD transition and a senescence-associated secretory phenotype.5Gerhardt L.M.S. Liu J. Koppitch K. et al.Single-nuclear transcriptomics reveals diversity of proximal tubule cell states in a dynamic response to acute kidney injury.Proc Natl Acad Sci U S A. 2021; 118e2026684118Google Scholar,6Kirita Y. Wu H. Uchimura K. et al.Cell profiling of mouse acute kidney injury reveals conserved cellular responses to injury.Proc Natl Acad Sci U S A. 2020; 117: 15874-15883Google Scholar G2-M phase cell cycle arrest and activation of cyclin G1 pathways in injured tubules has been associated with the formation of target of rapamycin-autophagy spatial coupling compartments and cytokine production,8Yang L. Besschetnova T.Y. Brooks C.R. et al.Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury.Nat Med. 2010; 16 (1p following 143): 535-543Google Scholar,9Canaud G. Brooks C.R. Kishi S. et al.Cyclin G1 and TASCC regulate kidney epithelial cell G2-M arrest and fibrotic maladaptive repair.Sci Transl Med. 2019; 11eaav4754Google Scholar although no evidence of G2-M phase arrest was found in proinflammatory subpopulations of injured proximal tubule cells in single-nucleus cell RNA-sequencing studies.5Gerhardt L.M.S. Liu J. Koppitch K. et al.Single-nuclear transcriptomics reveals diversity of proximal tubule cell states in a dynamic response to acute kidney injury.Proc Natl Acad Sci U S A. 2021; 118e2026684118Google Scholar Proliferative repair itself may impose an energy burden on dividing tubule cells that correlates with decreased expression of mitochondrial genes and increased susceptibility to cell injury.10Galichon P. Lannoy M. Li L. et al.Kidney epithelial proliferation impairs cell viability via energy depletion.bioRxiv. 2021; Google Scholar Although the proximal tubule is the nephron segment most acutely sensitive to AKI, single-cell and spatial transcriptomics also reveal gene expression changes in more distal segments (thick ascending limb and distal convoluted tubule) for the injury markers Umod and Lcn2.6Kirita Y. Wu H. Uchimura K. et al.Cell profiling of mouse acute kidney injury reveals conserved cellular responses to injury.Proc Natl Acad Sci U S A. 2020; 117: 15874-15883Google Scholar,7Dixon E. Wu H. Muto Y. et al.Spatially resolved transcriptomic analysis of acute kidney injury in a female murine model.J Am Soc Nephrol. 2022; 33: 279-289Google Scholar Nontubule cell types, including peritubular capillary endothelial cells and vascular pericytes, are also central to recovery from injury. Recent work has shown that failure to reconstitute proximal tubule capillary networks may be a better predictor of CKD with reduced glomerular filtration rate than kidney fibrosis in multiple AKI models (IRI, cisplatin, and rhabdomyolysis).11Menshikh A. Scarfe L. Delgado R. et al.Capillary rarefaction is more closely associated with CKD progression after cisplatin, rhabdomyolysis, and ischemia-reperfusion-induced AKI than renal fibrosis.Am J Physiol Renal Physiol. 2019; 317: F1383-F1397Google Scholar Analysis of the PTC enhancer and superenhancer landscape has also identified transcription factors associated with kidney repair, including Hnf4A, Gr, Stat3, Stat5, and Bet proteins. Inhibition of bromodomain-containing protein 4 function with the Bet inhibitor JQ1 impaired AKI recovery and increased mortality while reducing fibrosis, revealing an important role of bromodomain-containing proteins in multiple aspects of repair.12Wilflingseder J. Willi M. Lee H.K. et al.Enhancer and super-enhancer dynamics in repair after ischemic acute kidney injury.Nat Commun. 2020; 11: 3383Google Scholar Translational profiling studies revealed a strong upregulation of FoxM1, which can act as an oncogene, after kidney injury.13Chang-Panesso M. Kadyrov F.F. Lalli M. et al.FOXM1 drives proximal tubule proliferation during repair from acute ischemic kidney injury.J Clin Invest. 2019; 129: 5501-5517Google Scholar FoxM1 siRNA knockdown reduced epidermal growth factor–induced proliferation in cultured human PTCs, supporting a role in PTC proliferation. RNA-sequencing data sets for many of these experiments and others are available for download at the RBK data hub site.14Kesselman C. Pearlman L. Tangmunarunkit H. et al.GUDMAP/RBK User Guide (version 1) [data set].2017https://doi.org/10.25548/01-A00Google Scholar Figure 2 demonstrates how RBK data hub RNA-sequencing data sets from a unilateral ureteral obstruction model allow for the visualization of annotated clusters. For instance, these data confirm that the chemokine CC chemokine ligand (Ccl) 2 is primarily expressed in dedifferentiated proximal tubule cells, whereas CC chemokine receptors 2 and 4 are expressed in macrophages and activated fibroblasts, suggesting signaling relationships between these cell types that drive fibrosis. These data are part of a larger set of single-nucleus RNA-sequencing and single-cell RNA-sequencing data from healthy and fibrotic (unilateral ureteral obstruction) mice kidneys and are accessible for further analyses at the RBK data hub (Figure 3).15Wu H. Kirita Y. Donnelly E.L. et al.Advantages of single-nucleus over single-cell RNA sequencing of adult kidney: rare cell types and novel cell states revealed in fibrosis.J Am Soc Nephrol. 2019; 30: 23-32Google ScholarFigure 3Demonstrating how to access the (Re)Building a Kidney (RBK) data for analysis. The data shown in Figure 2 are available for access from the RBK's data repository (www.rebuilidingakidney.org). To access it, navigate to the DOI: https://doi.org/10.25548/14-4KG6. (a) Once on the Collection page, click the "View" icon under the Sequencing Study Collection. This will navigate you to the Study Detail page. (b) On the Study Detail page, one can access details on the experiment(s), the study analysis files (e.g., t-distributed stochastic neighbor embedding images), and replicate-level files (including the raw fastq or bam files) available for download. To learn more about using the RBK data repository, visit our documentation at https://www.doi.org/10.25548/01-A001 (or click Help in the menu on www.rebuildingakidney.org). The documentation contains instructions on how to use the RBK data browser, including instructive videos on how to find data. To access other types of RBK data, including sequencing, imaging, cell lines, metabolomics, antibody validations, protocols, and more, visit www.rebuildingakidney.org.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Zebrafish have been increasingly used as an AKI model. The zebrafish kidney provides insights into 2 modes of renal regeneration: (i) tubule repair and regeneration and (ii) stem cell–mediated, new nephron formation (Figure 4).16Tang Q. Iyer S. Lobbardi R. et al.Dissecting hematopoietic and renal cell heterogeneity in adult zebrafish at single-cell resolution using RNA sequencing.J Exp Med. 2017; 214: 2875-2887Google Scholar AKI studies of intrinsic tubule cell repair in the larval zebrafish pronephros have been useful for modeling mammalian AKI and performing small-molecule screening studies.17Skrypnyk N.I. Sanker S. Skvarca L.B. et al.Delayed treatment with PTBA analogs reduces postinjury renal fibrosis after kidney injury.Am J Physiol Renal Physiol. 2016; 310: F705-F716Google Scholar,18Cianciolo Cosentino C. Skrypnyk N.I. Brilli L.L. et al.Histone deacetylase inhibitor enhances recovery after AKI.J Am Soc Nephrol. 2013; 24: 943-953Google Scholar Gentamicin injection causes acute renal failure in larvae, with histologic and functional changes consistent with aminoglycoside toxicity in mammals.19Hentschel D.M. Park K.M. Cilenti L. et al.Acute renal failure in zebrafish: a novel system to study a complex disease.Am J Physiol Renal Physiol. 2005; 288: F923-F929Google Scholar Similar to mammalian kidneys, injured larval pronephric kidneys express kim-1/havcr1 and have similar pathophysiological responses during tubular injury, including loss of cell polarity, reactivation of pax2 expression, and induction of vimentin, indicating a conserved epithelial-to-mesenchymal transition during tubular injury.20Brilli Skvarca L. Han H.I. Espiritu E.B. et al.Enhancing regeneration after acute kidney injury by promoting cellular dedifferentiation in zebrafish.Dis Model Mech. 2019; 12dmm037390Google Scholar In addition, the larval AKI model can be utilized to screen for therapeutic candidates, and compound efficacy translates well to mammalian AKI models.17Skrypnyk N.I. Sanker S. Skvarca L.B. et al.Delayed treatment with PTBA analogs reduces postinjury renal fibrosis after kidney injury.Am J Physiol Renal Physiol. 2016; 310: F705-F716Google Scholar These therapeutic studies allow for rapid first-pass screening without requiring studies of compound pharmacokinetics as is needed in mammalian models.17Skrypnyk N.I. Sanker S. Skvarca L.B. et al.Delayed treatment with PTBA analogs reduces postinjury renal fibrosis after kidney injury.Am J Physiol Renal Physiol. 2016; 310: F705-F716Google Scholar In the adult zebrafish kidney, overall body growth and AKI induced the generation of new nephrons from adult stem cells in a process termed neonephrogenesis.21Diep C.Q. Ma D. Deo R.C. et al.Identification of adult nephron progenitors capable of kidney regeneration in zebrafish.Nature. 2011; 470: 95-100Google Scholar, 22Kamei C.N. Gallegos T.F. Liu Y. et al.Wnt signaling mediates new nephron formation during zebrafish kidney regeneration.Development. 2019; 146: dev168294Google Scholar, 23Gallegos T.F. Kamei C.N. Rohly M. et al.Fibroblast growth factor signaling mediates progenitor cell aggregation and nephron regeneration in the adult zebrafish kidney.Dev Biol. 2019; 454: 44-51Google Scholar New nephrons connect to preexisting distal tubules, replicating mesonephric development.21Diep C.Q. Ma D. Deo R.C. et al.Identification of adult nephron progenitors capable of kidney regeneration in zebrafish.Nature. 2011; 470: 95-100Google Scholar,22Kamei C.N. Gallegos T.F. Liu Y. et al.Wnt signaling mediates new nephron formation during zebrafish kidney regeneration.Development. 2019; 146: dev168294Google Scholar Adult kidney stem cells have been identified by 2 methods: transplantation of cells marked by Tg(lhx1a:EGFP) expression21Diep C.Q. Ma D. Deo R.C. et al.Identification of adult nephron progenitors capable of kidney regeneration in zebrafish.Nature. 2011; 470: 95-100Google Scholar and single cell RNA seq (scRNAseq) clustering of adult kidney cells that express the nephrogenic mesenchyme markers six2a, eya4, and osr1.16Tang Q. Iyer S. Lobbardi R. et al.Dissecting hematopoietic and renal cell heterogeneity in adult zebrafish at single-cell resolution using RNA sequencing.J Exp Med. 2017; 214: 2875-2887Google Scholar On injury, these cells expand in number, migrate, and aggregate as domed clusters on existing tubules to form nephron precursors (Figure 4)21Diep C.Q. Ma D. Deo R.C. et al.Identification of adult nephron progenitors capable of kidney regeneration in zebrafish.Nature. 2011; 470: 95-100Google Scholar,22Kamei C.N. Gallegos T.F. Liu Y. et al.Wnt signaling mediates new nephron formation during zebrafish kidney regeneration.Development. 2019; 146: dev168294Google Scholar in a process requiring fibroblast growth factor (chemotaxis and cell polarization23Gallegos T.F. Kamei C.N. Rohly M. et al.Fibroblast growth factor signaling mediates progenitor cell aggregation and nephron regeneration in the adult zebrafish kidney.Dev Biol. 2019; 454: 44-51Google Scholar) and Wnt signaling (nephron patterning and cell proliferation22Kamei C.N. Gallegos T.F. Liu Y. et al.Wnt signaling mediates new nephron formation during zebrafish kidney regeneration.Development. 2019; 146: dev168294Google Scholar). Although mammalian kidneys lack adult stem cell–mediated repair, both fish and mammals activate growth factor expression after injury,24Cirio M.C. de Groh E.D. de Caestecker M.P. et al.Kidney regeneration: common themes from the embryo to the adult.Pediatr Nephrol. 2014; 29: 553-564Google Scholar which has been associated with both proregenerative and profibrotic, context-specific effects.25Little M.H. Kairath P. Does renal repair recapitulate kidney development?.J Am Soc Nephrol. 2017; 28: 34-46Google Scholar Nonetheless, the zebrafish model indicates that a proregenerative growth factor environment along with responsive nephrogenic cells can lead to new nephron formation in an adult kidney. Mouse studies showed that tubular repair following AKI is largely, if not exclusively, mediated through replication of surviving proximal tubule cells with no strong evidence for contribution by a reparative cell type.26Humphreys B.D. Valerius M.T. Kobayashi A. et al.Intrinsic epithelial cells repair the kidney after injury.Cell Stem Cell. 2008; 2: 284-291Google Scholar,27Humphreys B.D. Czerniak S. DiRocco D.P. et al.Repair of injured proximal tubule does not involve specialized progenitors.Proc Natl Acad Sci U S A. 2011; 108: 9226-9231Google Scholar Tubule repair occurs via a Pik3c3-mediated mechanism that involves sensing of amino acid availability and initiating hypertrophic growth of PTCs by activation of the MTORC1-S6K1-rpS6 signaling pathway.28Liu T. Yuan J. Dai C. et al.Cre/loxP approach-mediated downregulation of Pik3c3 inhibits the hypertrophic growth of renal proximal tubule cells.J Cell Physiol. 2020; 235: 9958-9973Google Scholar Furthermore, lineage analysis of Slc34A1-expressing PTCs suggests fully differentiated cells reenter mitosis to directly replace PTCs after AKI.29Liu J. Krautzberger A.M. Sui S.H. et al.Cell-specific translational profiling in acute kidney injury.J Clin Invest. 2014; 124: 1242-1254Google Scholar In contrast, analysis of Fluorescence Ubiquitin Cell Cycle Indicator (FUCCI) transgenic mice, which visualize the cell cycle state, suggested that after injury, proximal tubule cells undergo endocycle progression to S phase, failing to divide, whereas a small subset of Pax2+/Havcr1– (Kim1–) tubular cells undergo clonal expansion for repair.30Lazzeri E. Angelotti M.L. Peired A. et al.Endocycle-related tubular cell hypertrophy and progenitor proliferation recover renal function after acute kidney injury.Nat Commun. 2018; 9: 1344Google Scholar Countering this suggestion, analysis of DNA content in Havcr1+ PTCs indicated that the bulk of cells have a 2N DNA content, arguing against extensive endocycling.31Chang-Panesso M. Humphreys B.D. Cellular plasticity in kidney injury and repair.Nat Rev Nephrol. 2017; 13: 39-46Google Scholar Recognizing alternative interpretations of these results, several RBK groups combined genetic strategies with cell profiling to characterize the AKI response and outcomes in the mouse kidney. Kusaba et al. created an estrogen-regulated Cre recombinase (CreERT2) knock-in mouse at the Kim1/Havcr1 locus and performed clonal analysis of injured Kim1+ cells.3Kusaba T. Lalli M. Kramann R. et al.Differentiated kidney epithelial cells repair injured proximal tubule.Proc Natl Acad Sci U S A. 2014; 111: 1527-1532Google Scholar Interestingly, Kim1/Havcr1+ cells undergo clonal expansion during repair, counter to a model in which repair is directed by a minor Pax2+/Kim1 intratubular progenitor type. Moreover, the acutely injured, genetically labeled clones coexpressed Kim1, vimentin, Sox8, and KI67, indicating a dedifferentiated and proliferative state.13Chang-Panesso M. Kadyrov F.F. Lalli M. et al.FOXM1 drives proximal tubule proliferation during repair from acute ischemic kidney injury.J Clin Invest. 2019; 129: 5501-5517Google Scholar In glomeruli, terminally differentiated podocytes cannot self-renew,32Shankland S.J. Freedman B.S. Pippin J.W. Can podocytes be regenerated in adults?.Curr Opin Nephrol Hypertens. 2017; 26: 154-164Google Scholar whereas endothelial, mesangial, and parietal epithelial cells (PECs) can. Although there is currently no known stem/progenitor cell for glomerular endothelial cells, cells of renin and neural/glial antigen 2+ (NG2+) lineage can partially replace mesangial cells and PECs.33Suzuki T. Eng D.G. McClelland A.D. et al.Cells of NG2 lineage increase in glomeruli of mice following podocyte depletion.Am J Physiol Renal Physiol. 2018; 315: F1449-F1464Google Scholar A decrease in podocyte cell number drives the magnitude of glomerular scarring and proteinuria, and even small increases in podocyte number can limit scarring,32Shankland S.J. Freedman B.S. Pippin J.W. Can podocytes be regenerated in adults?.Curr Opin Nephrol Hypertens. 2017; 26: 154-164Google Scholar which might be considered a clinical goal. Candidate podocyte progenitors include cells of renin lineage and PECs. In addition to their well-known endocrine function, cells of renin lineage are also multipotent stem cells. Lineage tracing studies show that cells of renin lineage can differentiate to a podocyte fate, a process that can be augmented with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers.34Lichtnekert J. Kaverina N.V. Eng D.G. et al.Renin-angiotensin-aldosterone system inhibition increases podocyte derivation from cells of renin lineage.J Am Soc Nephrol. 2016; 27: 3611-3627Google Scholar PECs are another adult podocyte progenitor source in disease that can differentiate to a podocyte fate, which can be augmented by several therapies.35Romoli S. Angelotti M.L. Antonelli G. et al.CXCL12 blockade preferentially regenerates lost podocytes in cortical nephrons by targeting an intrinsic podocyte-progenitor feedback mechanism.Kidney Int. 2018; 94: 1111-1126Google Scholar PECs are specialized cells lining the glomerular capsule and exist in different subpopulation. Even though not conclusively shown, PECs appear to constitute their own cellular niche, which can self-renew and be amplified on stress or disease.36D'Agati V.D. Shankland S.J. Recognizing diversity in parietal epithelial cells.Kidney Int. 2019; 96: 16-19Google Scholar,37Kuppe C. Leuchtle K. Wagner A. et al.Novel parietal epithelial cell subpopulations contribute to focal segmental glomerulosclerosis and glomerular tip lesions.Kidney Int. 2019; 96: 80-93Google Scholar RBK consortium studies are focused on better understanding the mechanisms of podocyte regeneration by cells of renin lineage and PEC progenitors and developing tools to aid in this investigation. In AKI, renal ischemia triggers a cascade of cellular injury and extracellular matrix (ECM) production. By isolating the ECM binding domains of naturally occurring growth and hemostatic factors, native and fibrotic kidney ECM may be targeted. Collagen-binding peptides isolated from decorin by White et al. demonstrated 2 times greater biodistribution to healthy kidneys via i.v. injection and 5 times greater biodistribution to a fibrotic kidney (7 days after unilateral ureteral obstruction).38White MJV, Ozkan M, Rączy MM, et al. Blocking antibodies against integrin-α3, integrin-αM, and integrin-αMβ2 de-differentiate myofibroblasts and reverse lung and kidney fibroses in a mouse model. bioRxiv. Published September 13, 2021. https://doi.org/10.1101/2021.06.07.447405Google Scholar Moreover, blocking antibodies against 3 different subtypes of integrins led to dedifferentiation of myofibroblasts and the reversal of fibrosis in the unilateral ureteral obstruction kidney.38White MJV, Ozkan M, Rączy MM, et al. Blocking antibodies against integrin-α3, integrin-αM, and integrin-αMβ2 de-differentiate myofibroblasts and reverse lung and kidney fibroses in a mouse model. bioRxiv. Published September 13, 2021. https://doi.org/10.1101/2021.06.07.447405Google Scholar Continuing studies examining how kidney injury and disease states change the ability of various ECM-binding peptides to target the kidney provide an opportunity to exploit CKD-related pathology for therapeutic advantage. RBK transcriptomic analysis of AKI is also directing approaches to therapy. The "failed repair" cell state associated with AKI in mice after IRI has now been defined by unique molecular markers and activated signaling pathways.5Gerhardt L.M.S. Liu J. Koppitch K. et al.Single-nuclear transcriptomics reveals diversity of proximal tubule cell states in a dynamic response to acute kidney injury.Proc Natl Acad Sci U S A. 2021; 118e2026684118Google Scholar,6Kirita Y. Wu H. Uchimura K. et al.Cell profiling of mouse acute kidney injury reveals conserved cellular responses to injury.Proc Natl Acad Sci U S A. 2020; 117: 15874-15883Google Scholar,8Yang L. Besschetnova T.Y. Brooks C.R. et al.Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury.Nat Med. 2010; 16 (1p following 143): 535-543Google Scholar Elimination of failed repair–PTCs using senolytic approaches has strong potential to benefit patient outcomes after AKI.39Wang M. Senolytics for kidney repair.Nat Rev Nephrol. 2021; 17: 512Google Scholar Small-molecule screens using the zebrafish model of larval AKI have also identified lead therapeutic compounds that have been validated in mouse models of AKI.17Skrypnyk N.I. Sanker S. Skvarca L.B. et al.Delayed treatment with PTBA analogs reduces postinjury renal fibrosis after kidney injury.Am J Physiol Renal Physiol. 2016; 310: F705-F716Google Scholar,20Brilli Skvarca L. Han H.I. Espiritu E.B. et al.Enhancing regeneration after acute kidney injury by promoting cellular dedifferentiation in zebrafish.Dis Model Mech. 2019; 12dmm037390Google Scholar Ongoing RBK studies of sex differences in susceptibility to CKD hold the potential to better define tailored treatments for AKI. Additional studies in progress aim to increase glomerular regeneration in vivo using cell-targeted delivery of novel peptides and small molecules to drive expansion and differentiation of PEC podocyte progenitors.36D'Agati V.D. Shankland S.J. Recognizing diversity in parietal epithelial cells.Kidney Int. 2019; 96: 16-19Google Scholar Kidney cell types all show varying potential for endogenous repair and tissue replacement. Countering these beneficial responses are nonproductive, proinflammatory cell states and limited availability of replacement progenitor cells. Using multiple models of injury, multi-omics approaches, and an open platform for data sharing, the RBK consortium aims to accelerate the pace of discovery and bring us closer to successfully repairing and regenerating injured kidneys.