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Inflammation and its timely resolution are critical to ensuring effective host defence and appropriate tissue repair after injury. Unresolved inflammation typifies many renal pathologies. The key drivers of the inflammatory response are well defined and targeted by conventional anti-inflammatory therapeutics. However, these are associated with undesirable side effects including immune suppression. More recently, there is growing appreciation that specialized lipid mediators [SPMs] including lipoxins promote the resolution of inflammation and endogenous repair mechanisms without compromising host defence. We discuss the pro-resolving bioactions of lipoxins and recent work that aims to harness their therapeutic potential in the context of kidney disease., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose of Review: Nephrology lacks effective therapeutics for many of the presentations and diseases seen in clinical practice. In recent decades, we have come to understand the central place of inflammation in initiating and propagating kidney disease, and, research in more recent years has established that the resolution of inflammation is a highly regulated and active process. With this, has evolved an appreciation that this aspect of the host inflammatory response is defective in kidney disease and led to consideration of a therapeutic paradigm aiming to harness the activity of the molecular drivers of the resolution phase of inflammation. Fatty-acid-derived Specialized pro-resolving mediators (SPMs), partly responsible for resolution of inflammation have gained traction as potential therapeutics., Recent Findings: We describe our current understanding of SPMs for this purpose in acute and chronic kidney disease. These studies cement the place of inflammation and its defective resolution in the pathogenesis of kidney disease, and highlight new avenues for therapy., Summary: Targeting resolution of inflammation is a viable approach to treating kidney disease. We optimistically look forward to translating these experimental advances into tractable therapeutics to treat kidney disease.

Inflammation and its timely resolution play a critical role in effective host defence and wound healing. Unresolved inflammatory responses underlie the pathology of many prevalent diseases resulting in tissue fibrosis and eventual organ failure as typified by kidney, lung and liver fibrosis. The role of autocrine and paracrine mediators including cytokines, prostaglandins and leukotrienes in initiating and sustaining inflammation is well established. More recently a physiological role for specialized pro-resolving lipid mediators [SPMs] in modulating inflammatory responses and promoting the resolution of inflammation has been appreciated. As will be discussed in this review, SPMs not only attenuate the development of fibrosis through promoting the resolution of inflammation but may also directly suppress fibrotic responses. These findings suggest novel therapeutic paradigms to treat intractable life-limiting diseases such as renal fibrosis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The advancement of microRNA (miRNA) therapies has been hampered by difficulties in delivering miRNA to the injured kidney in a robust and sustainable manner. Using bioluminescence imaging in mice with unilateral ureteral obstruction (UUO), we report that mesenchymal stem cells (MSCs), engineered to overexpress miRNA-let7c (miR-let7c-MSCs), selectively homed to damaged kidneys and upregulated miR-let7c gene expression, compared with nontargeting control (NTC)-MSCs. miR-let7c-MSC therapy attenuated kidney injury and significantly downregulated collagen IVα1, metalloproteinase-9, transforming growth factor (TGF)-β1, and TGF-β type 1 receptor (TGF-βR1) in UUO kidneys, compared with controls. In vitro analysis confirmed that the transfer of miR-let7c from miR-let7c-MSCs occurred via secreted exosomal uptake, visualized in NRK52E cells using cyc3-labeled pre-miRNA-transfected MSCs with/without the exosomal inhibitor, GW4869. The upregulated expression of fibrotic genes in NRK52E cells induced by TGF-β1 was repressed following the addition of isolated exosomes or indirect coculture of miR-let7c-MSCs, compared with NTC-MSCs. Furthermore, the cotransfection of NRK52E cells using the 3'UTR of TGF-βR1 confirmed that miR-let7c attenuates TGF-β1-driven TGF-βR1 gene expression. Taken together, the effective antifibrotic function of engineered MSCs is able to selectively transfer miR-let7c to damaged kidney cells and will pave the way for the use of MSCs for therapeutic delivery of miRNA targeted at kidney disease.

Diabetic nephropathy is the most common microvascular complication of diabetes mellitus, manifesting as mesangial expansion, glomerular basement membrane thickening, glomerular sclerosis, and progressive tubulointerstitial fibrosis leading to end-stage renal disease. Here we describe the functional characterization of Wnt6, whose expression is progressively lost in diabetic nephropathy and animal models of acute tubular injury and renal fibrosis. We have shown prominent Wnt6 and frizzled 7 (FzD7) expression in the mesonephros of the developing mouse kidney, suggesting a role for Wnt6 in epithelialization. Importantly, TCF/Lef reporter activity is also prominent in the mesonephros. Analysis of Wnt family members in human renal biopsies identified differential expression of Wnt6, correlating with severity of the disease. In animal models of tubular injury and fibrosis, loss of Wnt6 was evident. Wnt6 signals through the canonical pathway in renal epithelial cells as evidenced by increased phosphorylation of GSK3β (Ser9), nuclear accumulation of β-catenin and increased TCF/Lef transcriptional activity. FzD7 was identified as a putative receptor of Wnt6. In vitro Wnt6 expression leads to de novo tubulogenesis in renal epithelial cells grown in three-dimensional culture. Importantly, Wnt6 rescued epithelial cell dedifferentiation in response to transforming growth factor-β (TGF-β); Wnt6 reversed TGF-β-mediated increases in vimentin and loss of epithelial phenotype. Wnt6 inhibited TGF-β-mediated p65-NF-κB nuclear translocation, highlighting cross talk between the two pathways. The critical role of NF-κB in the regulation of vimentin expression was confirmed in both p65(-/-) and IKKα/β(-/-) embryonic fibroblasts. We propose that Wnt6 is involved in epithelialization and loss of Wnt6 expression contributes to the pathogenesis of renal fibrosis., (Copyright © 2016 the American Physiological Society.)

The role of inflammation in obesity-related pathologies is well established. We investigated the therapeutic potential of LipoxinA4 (LXA4:5(S),6(R),15(S)-trihydroxy-7E,9E,11Z,13E,-eicosatetraenoic acid) and a synthetic 15(R)-Benzo-LXA4-analog as interventions in a 3-month high-fat diet (HFD; 60% fat)-induced obesity model. Obesity caused distinct pathologies, including impaired glucose tolerance, adipose inflammation, fatty liver, and chronic kidney disease (CKD). Lipoxins (LXs) attenuated obesity-induced CKD, reducing glomerular expansion, mesangial matrix, and urinary H2O2. Furthermore, LXA4 reduced liver weight, serum alanine-aminotransferase, and hepatic triglycerides. LXA4 decreased obesity-induced adipose inflammation, attenuating TNF-α and CD11c(+) M1-macrophages (MΦs), while restoring CD206(+) M2-MΦs and increasing Annexin-A1. LXs did not affect renal or hepatic MΦs, suggesting protection occurred via attenuation of adipose inflammation. LXs restored adipose expression of autophagy markers LC3-II and p62. LX-mediated protection was demonstrable in adiponectin(-/-) mice, suggesting that the mechanism was adiponectin independent. In conclusion, LXs protect against obesity-induced systemic disease, and these data support a novel therapeutic paradigm for treating obesity and associated pathologies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Renal dysfunction and disease, including hyperfiltration, proteinuria and hypofiltration, are commonly associated with obesity. Diabetic kidney disease is also common in obese cohorts. Weight loss interventions, including bariatric surgery, can effectively reduce weight and improve renal outcomes. Some of this effect may be due to the remission of Type 2 diabetes and hypertension. However, other mechanisms, including the resolution of inflammatory processes, may also contribute. The effect of bariatric surgery on renal function has only recently become a focus of particular investigation. In this study, we will review the effects of bariatric surgery on obesity-associated kidney disease. We will discuss the pitfalls in assessing renal function in obese cohorts and will examine the effect of bariatric surgery on renal function and urinary protein excretion using different mechanisms. We will give particular attention to the evidence for bariatric surgery in cohorts with established renal disease and suggest future directions. In particular, we will outline the evidence for inflammation as an important therapeutic target, and the emerging medical therapies being considered to exploit this target in obesity- and diabetes-related kidney disease.

Unresolved inflammation underlies the development of fibrosis and organ failure. Here, we investigate the potential of the proresolving eicosanoid lipoxinA₄ (LXA₄) and its synthetic analog benzo-LXA₄ to prophylactically modulate fibrotic and inflammatory responses in a model of early renal fibrosis, unilateral ureteric obstruction (UUO). Male Wistar rats (Animalia, Chordata, Rattus norvegicus) were injected intravenously with vehicle (0.1% ethanol), LXA₄ (45 μg/250-g rat), or benzo-LXA₄ (15 μg/250-g rat) 15 min prior to surgery and sacrificed 3 d postligation. Renal gene and protein expression, collagen deposition, macrophage infiltration, and apoptosis were analyzed using manipulated kidneys from sham operations as control. Lipoxins (LXs) attenuated collagen deposition and renal apoptosis (P<0.05) and shifted the inflammatory milieu toward resolution, inhibiting TNF-α and IFN-γ expression, while stimulating proresolving IL-10. LXs attenuated UUO-induced activation of MAP kinases, Akt, and Smads (P<0.05) in injured kidneys. We explored whether the underlying mechanism reflected LX-induced modulation of fibroblast activation. Using cultured rat renal NRK-49F fibroblasts, we report that LXA₄ (1 nM) inhibits TGF-β1 (10 ng/ml)-induced activation of Smad2 and MAP-kinases (P<0.05), and furthermore, LXA₄ reduced TGF-β1-stimulated PAI-1 luciferase activation (P<0.05) relative to vehicle-stimulated cells. We propose that LXs may represent a potentially useful and novel therapeutic strategy for consideration in the context of renal fibrosis.

Inflammation is a common feature of renal pathology. Lipid mediators, such as lipoxins, resolvins, and protectins, can actively promote the resolution of inflammation by inhibiting polymorphonuclear cell infiltration to the site of inflammation, shifting the cytokine milieu from proinflammatory to proresolving and increasing the nonphlogistic phagocytosis of apoptotic cells by macrophages. Here we review the evidence for molecular circuits of resolution in renal disease.

Lipoxins are lipoxygenase-derived lipid mediators with both anti-inflammatory and proresolution properties that have been demonstrated in vivo and in vitro. The bioactivity profile of lipoxins in vitro suggests that they have therapeutic potential in acute renal failure and glomerulonephritis; predictions that have been borne out to date in experimental models of renal disease. We review recent developments on the molecular basis of lipoxin bioactions mediated through receptor crosstalk and the accumulating evidence that lipoxins may have potential as novel anti-inflammatory agents.

Background: Chronic kidney disease (CKD) is a complex disorder that has become a high prevalence global health problem, with diabetes being its predominant pathophysiologic driver. Autosomal genetic variation only explains some of the predisposition to kidney disease. Variations in the mitochondrial genome (mtDNA) and nuclear-encoded mitochondrial genes (NEMG) are implicated in susceptibility to kidney disease and CKD progression, but they have not been thoroughly explored. Our aim was to investigate the association of variation in both mtDNA and NEMG with CKD (and related traits), with a particular focus on diabetes. Methods: We used the UK Biobank (UKB) and UK-ROI, an independent collection of individuals with type 1 diabetes mellitus (T1DM) patients. Results: Fourteen mitochondrial variants were associated with estimated glomerular filtration rate (eGFR) in UKB. Mitochondrial variants and haplogroups U, H and J were associated with eGFR and serum variables. Mitochondrial haplogroup H was associated with all the serum variables regardless of the presence of diabetes. Mitochondrial haplogroup X was associated with end-stage kidney disease (ESKD) in UKB. We confirmed the influence of several known NEMG on kidney disease and function and found novel associations for SLC39A13, CFL1, ACP2 or ATP5G1 with serum variables and kidney damage, and for SLC4A1, NUP210 and MYH14 with ESKD. The G allele of TBC1D32-rs113987180 was associated with higher risk of ESKD in patients with diabetes (OR:9.879; CI95%:4.440–21.980; P = 2.0E-08). In UK-ROI, AGXT2-rs71615838 and SURF1-rs183853102 were associated with diabetic nephropathies, and TFB1M-rs869120 with eGFR. Conclusions: We identified novel variants both in mtDNA and NEMG which may explain some of the missing heritability for CKD and kidney phenotypes. We confirmed the role of MT-ND5 and mitochondrial haplogroup H on renal disease (serum variables), and identified the MT-ND5-rs41535848G variant, along with mitochondrial haplogroup X, associated with higher risk of ESKD. Despite most of the associations were independent of diabetes, we also showed potential roles for NEMG in T1DM. [ABSTRACT FROM AUTHOR]

High-throughput DNA testing is becoming established as a standard diagnostic test in the renal clinic. Previously published studies on cohorts of patients with unexplained chronic kidney disease of a suspected genetic aetiology have suggested a diagnostic yield for genomic sequencing of up to 18%. Here we determine the yield of targeted gene panel in a clinically unscreened cohort of patients referred for percutaneous native renal biopsy. Patients who underwent renal biopsy for investigation of chronic kidney disease were sequenced using a genomicsequencing panel covering 227 genes in which variation is known to be associated with monogenic chronic kidney disease (CKD). Candidate disease-causing variants were assessed for pathogenicity using guidelines from the American College for Medical Genetics and Genomics. Fifty CKD patients were recruited and sequenced. A molecular diagnosis was obtained for two patients (4%). A molecular diagnosis is possible using genomic testing in ~4% of clinically unscreened patients undergoing renal biopsy. Genetic screening may be useful for diagnosis in a subset of CKD patients but is most valuable when applied to patients with suspected heritable forms of kidney disease. [ABSTRACT FROM AUTHOR]

Induced in high glucose-1 (IHG-1) is a conserved mitochondrial protein associated with diabetic nephropathy (DN) that amplifies profibrotic transforming growth factor (TGF)-β1 signaling and increases mitochondrial biogenesis. Here we report that inhibition of endogenous IHG-1 expression results in reduced mitochondrial respiratory capacity, ATP production, and mitochondrial fusion. Conversely, overexpression of IHG-1 leads to increased mitochondrial fusion and also protects cells from reactive oxygen species-induced apoptosis. IHG-1 forms complexes with known mediators of mitochondrial fusion--mitofusins (Mfns) 1 and 2--and enhances the GTP-binding capacity of Mfn2, suggesting that IHG-1 acts as a guanine nucleotide exchange factor. IHG-1 must be localized to mitochondria to interact with Mfn1 and Mfn2, and this interaction is necessary for increased IHG-1-mediated mitochondrial fusion. Together, these findings indicate that IHG-1 is a novel regulator of both mitochondrial dynamics and bioenergetic function and contributes to cell survival following oxidant stress. We propose that in diabetic kidney disease increased IHG-1 expression protects cell viability and enhances the actions of TGF-β, leading to renal proximal tubule dedifferentiation, an important event in the pathogenesis of this devastating condition. [ABSTRACT FROM AUTHOR]

Up to 40% of patients with type 1 and type 2 diabetes will develop diabetic nephropathy (DN), resulting in chronic kidney disease and potential organ failure. There is evidence for a heritable genetic susceptibility to DN, but despite intensive research efforts the causative genes remain elusive. Recently, genome-wide association studies have discovered several novel genetic variants associated with DN. The identification of such variants may potentially allow for early identification of at risk patients. Here we review the current understanding of the key molecular mechanisms and genetic architecture of DN, and discuss the merits of employing an integrative approach to incorporate datasets from multiple sources (genetics, transcriptomics, epigenetic, proteomic) in order to fully elucidate the genetic elements contributing to this serious complication of diabetes. [ABSTRACT FROM AUTHOR]

Background: CCN2/CTGF is an established effector of TGFβ driven responses in diabetic nephropathy. We have identified an interaction between CCN2 and TGFβ leading to altered phenotypic differentiation and inhibited cellular migration. Here we determine the gene expression profile associated with this phenotype and define a transcriptional basis for differential actin related gene expression and cytoskeletal function. Results: From a panel of genes regulated by TGFβ and CCN2, we used co-inertia analysis to identify and then experimentally verify a subset of transcription factors, E2F1 and CREB, that regulate an expression fingerprint implicated in altered actin dynamics and cell hypertrophy. Importantly, actin related genes containing E2F1 and CREB binding sites, stratified by expression profile within the dataset. Further analysis of actin and cytoskeletal related genes from patients with diabetic nephropathy suggests recapitulation of this programme during the development of renal disease. The Rho family member Cdc42 was also found uniquely to be activated in cells treated with TGFβ and CCN2; Cdc42 interacting genes were differentially regulated in diabetic nephropathy. Conclusions: TGFβ and CCN2 attenuate CREB and augment E2F1 transcriptional activation with the likely effect of altering actin cytoskeletal and cell growth/hypertrophic gene activity with implications for cell dysfunction in diabetic kidney disease. The cytoskeletal regulator Cdc42 may play a role in this signalling response. [ABSTRACT FROM AUTHOR]

Signalling interplay between transforming growth factor-b (TGFb) and CCN2 [also called connective tissue growth factor (CTGF)] plays a crucial role in the progression of diabetic nephropathy and has been implicated in cellular differentiation. To investigate the potential role of microRNAs (miRNAs) in the mediation of this signalling network, we performed miRNA screening in mesangial cells treated with recombinant human CCN2. Analysis revealed a cohort of 22 miRNAs differentially expressed by twofold or more, including members of the miR-302 family. Target analysis of miRNA to 39-untranslated regions (39-UTRs) identified TGFb receptor II (TbRII) as a potential miR-302 target. In mesangial cells, decreased TbRII expression was confirmed in response to CCN2 together with increased expression of miR-302d. TbRII was confirmed as an miR-302 target, and inhibition of miR-302d was sufficient to attenuate the effect of CCN2 on TbRII. Data from the European Renal cDNA Biopsy Bank revealed decreased TbRII in diabetic patients, suggesting pathophysiological significance. In a mouse model of fibrosis (UUO), miR-302d was increased, with decreased TbRII expression and aberrant signalling, suggesting relevance in chronic fibrosis. miR-302d decreased TGFb-induced epithelial mesenchymal transition (EMT) in renal HKC8 epithelial cells and attenuated TGFb-induced mesangial production of fibronectin and thrombospondin. In summary, we demonstrate a new mode of regulation of TGFb by CCN2, and conclude that the miR-302 family has a role in regulating growth factor signalling pathways, with implications for nephropathic cell fate transitions. [ABSTRACT FROM AUTHOR]

The role of inflammation in the pathogenesis of type 2 diabetes mellitus (T2DM) and its associated complications is increasingly recognized. The resolution of inflammation is actively regulated by endogenously produced lipid mediators such as lipoxins, resolvins, protectins, and maresins. Here we review the potential role of these lipid mediators in diabetes-associated pathologies, specifically focusing on adipose inflammation and diabetic kidney disease, i.e., diabetic nephropathy (DN). DN is one of the major complications of T2DM and we propose that pro-resolving lipid mediators may have therapeutic potential in this context. Adipose inflammation is also an important component of T2DM-associated insulin resistance and altered adipokine secretion. Promoting the resolution of adipose inflammation would therefore likely be a beneficial therapeutic approach in T2DM. [ABSTRACT FROM AUTHOR]

Developmental processes are regulated by the bone morphogenetic protein (BMP) family of secreted molecules. BMPs bind to serine/threonine kinase receptors and signal through the canonical Smad pathway and other intracellular effectors. Integral to the control of BMPs is a diverse group of secreted BMP antagonists that bind to BMPs and prevent engagement with their cognate receptors. Tight temporospatial regulation of both BMP and BMP-antagonist expression provides an exquisite control system for developing tissues. Additional facets of BMP-antagonist biology, such as crosstalk with Wnt and Sonic hedgehog signaling during development, have been revealed in recent years. In addition, previously unappreciated roles for the BMP antagonists in kidney fibrosis and cancer have been elucidated. This review provides a description of BMP-antagonist biology, together with highlights of recent novel insights into the role of these antagonists in development, signal transduction and human disease. [Copyright &y& Elsevier]

OBJECTIVE--Gremlin (grem1) is an antagonist of the bone morphogenetic protein family that plays a key role in limb bud development and kidney formation. There is a growing appreciation that altered grem1 expression may regulate the homeostatic constraints on damage responses in diseases such as diabetic nephropathy. RESEARCH DESIGN AND METHODS--Here we explored whether knockout mice heterozygous for grem1 gene deletion (grem1 +/-) exhibit protection from the progression of diabetic kidney disease in a streptozotocin-induced model of type 1 diabetes. RESULTS--A marked elevation in grem1 expression was detected in the kidneys and particularly in kidney tubules of diabetic wild-type mice compared with those of littermate controls. In contrast, diabetic grem1[sup +/-] mice displayed a significant attenuation in grem1 expression at 6 months of diabetes compared with that in age- and sex-matched wild-type controls. Whereas the onset and induction of diabetes were similar between grem1[sup +/-] and wild-type mice, several indicators of diabetes-associated kidney damage such as increased glomerular basement membrane thickening and microalbuminuria were attenuated in grem1[sup +/-] mice compared with those in wild-type controls. Markers of renal damage such as fibronectin and connective tissue growth factor were elevated in diabetic wildtype but not in grem1[sup +/-] kidneys. Levels of pSmadl/5/8 decreased in wild-type but not in grem1[sup +/-] diabetic kidneys, suggesting that bone morphogenetic protein signaling may be maintained in the absence of grem1. CONCLUSIONS--These data identify grem1 as a potential modifier of renal injury in the context of diabetic kidney disease. Diabetes 58:1641-1650, 2009 [ABSTRACT FROM AUTHOR]

The molecular pathogenesis of diabetic nephropathy (DN), the leading cause of end-stage renal disease worldwide, is complex and not fully understood. Transforming growth factor-β (TGF-β1) plays a critical role in many fibrotic disorders, including DN. In this study, we report protein kinase B (PKB/Akt) activation as a downstream event contributing to the pathophysiology of DN. We investigated the potential of PKB/Akt to mediate the profibrotic bioactions of TGF-β1 in kidney. Treatment of normal rat kidney epithelial cells (NRK52E) with TGF-β1 resulted in activation of phosphatidylinositol 3-kinase (PIK) and PKB/Akt as evidenced by increased Ser473 phosphorylation and GSK-3β phosphorylation. TGF-β1 also stimulated increased Smad3 phosphorylation in these cells, a response that was insensitive to inhibition of PβK or PKB/Akt. NRK52E cells displayed a loss of zona occludins 1 and E-cadherin and a gain in vimentin and α-smooth muscle actin expression, consistent with the fibrotic actions of TGF-β1. These effects were blocked with inhibitors of PβK and PKB/Akt. Furthermore, overexpression of PTEN, the lipid phosphatase regulator of PKB/Akt activation, inhibited TGF-β1-induced PKB/Akt activation. Interestingly, in the Goto-Kakizaki rat model of type 2 diabetes, we also detected increased phosphorylation of PKB/Akt and its downstream target, GSK-3β, in the tubules, relative to that in control Wistar rats. Elevated Smad3 phosphorylation was also detected in kidney extracts from Goto-Kakizaki rats with chronic diabetes. Together, these data suggest that TGF-β1-mediated PKB/Akt activation may be important in renal fibrosis during diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Fibroblast proliferation is central to the evolution of renal tubulointerstitial fibrosis. Using both in vivo and in vitro approaches, Sörensen et al. describe a role for fibrinogen as a cell-surface-receptor-mediated mitogen for renal fibroblasts. This interaction, likely to be initiated by injury and extravasation and to signal principally via Toll-like receptors, implicates fibrinogen in renal fibrosis beyond its textbook description as a scaffold precursor at the end of the coagulation cascade. [ABSTRACT FROM AUTHOR]

DNA oligonucleotide microarray technology identifies fisp-12 among other potential fibrogenic genes following murine unilateral ureteral obstruction (UUO): Modulation during epithelial-mesenchymal transition. Background. Tubulointerstitial inflammation and fibrosis are pathologic hallmarks of end-stage renal disease (ESRD). Here we have used DNA microarray technology to monitor the transcriptomic responses to murine unilateral ureteral obstruction (UUO) with a view to identifying molecular modulators of tubulointerstitial fibrosis. Methods. Using Affymetrix Mu74Av2 microarrays, gene expression 4 and 10 days postobstruction was investigated relative to control contralateral kidneys. Candidate profibrogenic genes were further investigated in epithelial cells undergoing epithelial to mesenchymal transition (EMT) in vitro. Results. mRNA levels for 1091 gene/EST sequences, of a total of 12,488 displayed on the microarray, were altered twofold or greater by days 4 and 10 postobstruction compared to contralateral control kidneys. Genes were categorised into functional groups, including modulators of cytoskeletal and extracellular matrix metabolism, cell growth, signalling, and transcription/translational events. Among the potentially profibrogenic genes, whose mRNA levels were increased after UUO, were fibroblast-inducible secreted protein (fisp-12), the murine homologue of connective tissue growth factor (CTGF), collagen XVIIIα1, secreted protein acidic and rich in cysteine (SPARC), and src-suppressed C-kinase substrate (SSeCKS). A sustained increase in fisp-12 mRNA level was observed during EMT induced by transforming growth factor-β1 (TGF-β1) and epidermal growth factor (EGF). Conclusion. Altered gene expression in murine UUO has been demonstrated. Increased expression of fisp-12, SPARC, and SSeCKS has been shown in response to TGF-β1 treatment and during EMT, suggesting that these genes may offer potential therapeutic targets against tubulointerstitial fibrosis. [ABSTRACT FROM AUTHOR]