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Objective·To investigate the effect of icariin on the transition from acute kidney disease (AKI) to chronic kidney disease (CKD) in mice and the possible mechanism.Methods·C57BL/6 mice were intraperitoneally injected with aristolochic acid for 2 weeks to mimic AKI to CKD transition. Icariin was intragastrically administered for 2 or 5 weeks at the end of 2 weeks of aristolochic acid injection or 1 week before modeling. The renal function and pathological injury of the mice were monitored. The mitochondrial structure of renal tubular epithelial cells was observed by transmission electron microscopy. The indexes related to fatty acid oxidative metabolic pathway, fibrosis, and inflammation were detected by quantitative PCR (qPCR) and immunohistochemical staining. The rat renal fibroblast cell line and the rat renal tubular epithelial cell lines were co-cultured in Transwell cell chambers to simulate the interaction between the two types of cells. The renal tubular epithelial cells were pretreated with icariin for 1 h, and then treated with aristolochic acid for 24 h. After removing the two drugs, the renal tubular epithelial cells and the fibroblasts were co-cultured for 24 h. The mRNA or protein expression levels of peroxisome proliferator-activated receptor α (Ppara), pro-fibrotic factors, inflammatory factors, activated caspase-3 (cleaved caspase-3), and extracellular matrix-associated genes in renal fibroblasts were detected by qPCR or Western blotting. The renal tubular epithelial cells were transfected with Ppara-siRNA to observe the expression changes of cleaved caspase-3 and the related indicators of mitochondrial fatty acid oxidative metabolism in the downstream of PPARα after icariin intervention prior to aristolochic acid.Results·Compared with the control group, the serum creatinine and urea nitrogen levels of the mice injected with aristolochic acid only were significantly higher, with a large number of inflammatory cells infiltrating into the kidney and serious renal tubular injury at the end of 2 weeks of aristolochic acid injection and 2 weeks after the last injection (4 weeks). The renal function was significantly improved, and the pathological damage was attenuated in the mice pretreated with icariin. After 4 weeks of modeling, the mitochondrial structure of renal tubular epithelial cells was seriously damaged in the aristolochic acid group, and the mRNA levels of fatty acid oxidative metabolic pathway-related genes were significantly downregulated, compared to the control group, accompanied by macrophage infiltration and renal fibrosis. Icariin pretreatment attenuated these damages generated by aristolochic acid. The serum creatinine and urea nitrogen levels, renal pathological injury, and fibrotic markers of the mice treated with icariin at the end of 2 weeks of aristolochic acid injection showed no difference from the aristolochic acid group. In the in vitro experiments, aristolochic acid treatment suppressed Ppara mRNA expression and elevated cleaved caspase-3, inflammatory factors, and pro-fibrotic factors in renal tubular epithelial cells. It also upregulated the expression of extracellular matrix-related genes in co-cultured renal fibroblasts. In contrast, icariin pretreatment abrogated the changes caused by aristolochic acid. The knockdown of Ppara by siRNA in renal tubular epithelial cells removed the preventive effects of icariin on aristolochic acid inhibiting fatty acid oxidative metabolism and promoting cell apoptosis.Conclusion·Icariin prevents AKI to CKD transition induced by aristolochic acid in mice. It may play its protective role by improving the mitochondrial fatty acid oxidative metabolic pathway, especially through PPARα, in renal tubular epithelial cells.

Background This study investigates the link between genetic variants associated with kidney function and immunoglobulin A (IgA) nephropathy (IgAN) progression. Methods We recruited 961 biopsy-proven IgAN patients and 651 non-IgAN end-stage renal disease (ESRD) patients from Ruijin Hospital. Clinical and renal pathological data were collected. The primary outcome was the time to ESRD. A healthy population was defined as estimated glomerular filtration rate >60 mL/min/1.73 m2 without albuminuria or hematuria. Fifteen single-nucleotide polymorphisms (SNPs) were selected from a genome-wide association study of kidney function and genotyped by the SNaPshot. Immunohistochemistry in renal tissue and ELISA in urine samples were performed to explore the potential functions of genetic variations. Results The rs77924615-G was independently associated with an increased risk for ESRD in IgAN patients after adjustments for clinical and pathologic indices, and treatment (adjusted hazard ratio 2.10; 95% confidence interval 1.14–3.88). No significant differences in ESRD-free survival time were found among different genotypes in non-IgAN ESRD patients (log-rank, P = .480). Moreover, rs77924615 exhibited allele-specific enhancer activity by dual-luciferase reporter assay. Accordingly, the urinary uromodulin–creatinine ratio (uUCR) was significantly higher in healthy individuals with rs77924615 AG or GG than in individuals with AA. Furthermore, uromodulin expression in tubular epithelial cells was higher in patients with rs77924615 AG or GG. Finally, we confirmed that an increased uUCR (P = .009) was associated with faster IgAN progression. Conclusion The SNP rs77924615, which modulates the enhancer activity of the UMOD gene, is associated with renal function deterioration in IgAN patients by increasing uromodulin levels in both the renal tubular epithelium and urine. [ABSTRACT FROM AUTHOR]

Background Few studies have evaluated the treatment of immunoglobulin A nephropathy (IgAN) patients with nephrotic syndrome (NS) and mesangioproliferative glomerulonephritis (MPGN). The aim of this study was to compare the therapeutic effects of oral glucocorticoids (GCS) combined with intravenous cyclophosphamide (CTX) and oral GCS alone in the treatment of the MPGN-IgAN patients with NS. Methods Biopsy-proven primary IgAN patients who were aged ≥14 years at diagnosis, had coexistent NS and MPGN and estimated glomerular filtration rate (eGFR) ≥15 mL/min/1.73 m2, and were treated by oral GCS combined with intravenous CTX or oral GCS alone for 6–12 months were retrospectively included. The patients in the GCS + CTX (prednisone 0.6–0.8 mg/kg/day and intravenous CTX 0.6–1.0 g monthly) or GCS (prednisone 0.8–1 mg/kg/day) group were rather matched at a 1:1 ratio on key characteristics by propensity score matching. The primary outcome was defined as either complete remission or partial remission at Month 24. The secondary outcome was a composite renal endpoint defined as a 50% decline in eGFR, doubling of serum creatinine or progression to end-stage kidney disease. Results Among the 146 IgAN patients who met the inclusion criteria, 42 patients were enrolled in the GCS + CTX group, and 42 patients were enrolled in the GCS group after propensity score matching. The clinical and histological parameters were similar between the two groups. Remission occurred more frequently in the GCS + CTX group at Month 6 (88.1% vs 52.4%, P  < 0.001), Month 12 (88.1% vs 56.1%, P  = 0.001) and Month 24 (85.0% vs 47.5%, P  < 0.001) than in the GCS group. Moreover, subgroup analysis revealed that the higher response rate at Month 24 in the GCS + CTX group than in the GCS group was also present in different subgroups defined by sex, age, eGFR or Oxford MEST-C. Notably, we found that eGFR decreased at a lower rate in patients from the GCS + CTX group than in patients from the GCS group [eGFR slope: 0.05(–3.09, 3.67) vs –2.56 (–11.30, 0.86) mL/min/1.73 m2/year, P  = 0.03]. Based on multivariate Cox regression analysis, GCS + CTX treatment was found to be independently associated with a decrease in risk for the composite endpoint after adjusted by the International Risk Prediction Score with race (hazard ratio = 0.17, 95% confidence interval 0.04–0.83, P  = .03). There was no significant difference in adverse events (50.0% vs 42.9%, P  = 0.51) or serious adverse events (7.1% vs 11.9%, P  = .71) between the two groups. Conclusions Oral GCS combined with intravenous CTX is superior to GCS alone in treating MPGN-IgAN patients combined with NS. As the retrospective design and small sample size, our findings need to be validated by a prospective study. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is one of the most important risk factors for chronic and progressive kidney disease, leading to end-stage kidney failure. Tubule epithelial regeneration leads to the resolution of renal failure in AKI. Failure of tubule epithelial regeneration leads to concomitant hypoxia from loss of microcirculation, which serves as a critical factor leading to chronic kidney disease. In this issue of the JCI, Li et al. show that hypoxia activates the stress-responsive transcription factor FoxO3. Increased FoxO3 protein abundance leads to alterations in tubular epithelial autophagy and metabolism, highlighting an important mechanism causing permanent renal damage even after an acute injury., Thin line between acute kidney injury and chronic kidney disease A new categorization system for kidney diseases is long overdue. At present, we group diseases based on their temporal course, [...]

Background/Aims: Angiotensin II (Ang II) has been regarded as an important profibrogenic cytokine in renal fibrosis. Krüppel-like factor 15 (KLF15) has been identified as an important negative transcription factor in renal fibrosis. However, little is known about the role of KLF15 in Ang II-induced renal fibrosis. Methods: In this study, we randomized mice into a control group, Ang II group or Ang II plus losartan group. KLF15 expression was examined with real-time PCR and immunofluorescence in these groups. In vitro, KLF15 expression was examined by Western blot in rat renal fibroblasts (NRK-49F) stimulated with Ang II, and the effect of altered KLF15 expression on the regulation of the profibrotic factor connective tissue growth factor (CTGF) was further explored with co-immunoprecipitation (CoIP) and chromatin immunoprecipitation (ChIP) analyses. Results: Compared with the control group, the murine model of Ang II-induced renal fibrosis demonstrated a significant decrease in renal KLF15 expression at 4 weeks and presented with progressive renal fibrosis at 6 weeks. Meanwhile, losartan, an angiotensin type 1 (AT1) receptor antagonist, effectively prevented the downregulation of KLF15 expression induced by Ang II infusion. In vitro, NRK-49F cells stimulated with Ang II exhibited a significant decrease in KLF15 expression, accompanied by a marked increase in the expression of profibrotic factors and in the production of extracellular matrix. The up-regulation of CTGF expression induced by Ang II stimulation was inhibited by KLF15 overexpression in NRK-49F cells, and losartan treatment prevented the down-regulation of KLF15 expression and the up-regulation of CTGF expression induced by Ang II stimulation. Furthermore, CoIP and ChIP assays revealed that the transcription regulator KLF15 directly bound to the co-activator P/CAF and repressed its recruitment to the CTGF promoter. Conclusions: Ang II down-regulates KLF15 expression via the AT1 receptor, and KLF15 is likely to inhibit Ang II-induced CTGF expression by repressing the recruitment of the co-activator P/ CAF to the CTGF promoter. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is one of the most important risk factors for chronic and progressive kidney disease, leading to end-stage kidney failure. Tubule epithelial regeneration leads to the resolution of renal failure in AKI. Failure of tubule epithelial regeneration leads to concomitant hypoxia from loss of microcirculation, which serves as a critical factor leading to chronic kidney disease. In this issue of the JCI, Li et al. show that hypoxia activates the stress-responsive transcription factor FoxO3. Increased FoxO3 protein abundance leads to alterations in tubular epithelial autophagy and metabolism, highlighting an important mechanism causing permanent renal damage even after an acute injury. [ABSTRACT FROM AUTHOR]

Objective: To systematically assess the effects of individualized Chinese medicines on recurrent urinary tract infections (rUTIs)., Methods: This study recruited 230 adult female patients in the remission phase of rUTIs from five hospitals in China. The patients were randomly allocated to two groups: an individualized Chinese medicine group ( n = 114) and a control group ( n = 116). Patients in the Chinese medicine group received individualized Chinese herbs, which were evaluated for syndrome differentiation. Patients in the control group received antibiotic treatment combined with a Chinese medicine placebo. The duration of treatment was three courses of four weeks each, with a three-month subsequent follow-up. UTI recurrence rate, Traditional Chinese Medicine (TCM) syndrome scores, 36-item Short Form Survey (SF-36) score, and urine secretory immunoglobulin A (SIgA) were measured and analyzed before and after treatment in each group., Results: Patients from the Chinese medicine group exhibited significant decreases in both short- and long-term UTI recurrence rates compared with the control group ( P < 0.05). The changes in TCM syndrome scores between the Chinese medicine and control groups were significant ( P < 0.05). The changes in the average SF-36 quality-of-life scores in the Chinese medicine group were also significantly higher than those in the control group after treatment ( P < 0.05). The Chinese medicine group also demonstrated a significant increase in urine SIgA expression., Conclusion: Taken together, compared to the often-used long-term antimicrobial prophylaxis during the remission stage of rUTIs, treating patients with an individualized Chinese medicine decoction by syndrome differentiation could effectively reduce the recurrence rate, improve the patients' TCM syndrome scores and quality of life, and enhance immunity, which in turn helps to prevent antibiotic resistance.

Background/aims: Icariin plays an antifibrotic role in the unilateral ureteral obstruction (UUO) model; however, its primary mechanism has not been elucidated. G protein-coupled estrogen receptor (GPER) has been shown to be associated with fibrosis and mitochondrial biogenesis. In this study, we aimed to investigate the impact of GPER on renal fibrosis and whether icariin attenuates renal fibrosis dependent on GPER., Methods: In the in vivo study, 10-week-old mice were subjected to the UUO model followed by UUO with icariin, G-15 (a GPER antagonist), and icariin + G-15. GPER expression, renal fibrosis levels, and mitochondrial alterations were measured and analyzed. In an in vitro study, we examined the antifibrotic effect of icariin on rat renal fibroblasts (NRK-49F) via GPER., Results: Consistent with a previous study, icariin significantly attenuated fibrotic markers and protected the kidneys against mitochondrial injuries in the UUO model. However, G-15 exacerbated renal fibrosis and abolished the protective effect of icariin in the UUO model. Furthermore, antagonizing or knocking down GPER in NRK-49F significantly increased fibrotic markers and eliminated the antifibrotic effect of icariin., Conclusions: Our findings indicate that (1) GPER inhibition exacerbates renal fibrosis, and (2) icariin exerts antifibrotic effects against renal fibrosis through GPER., Competing Interests: None., (AJTR Copyright © 2022.)

Large epidemiological studies clearly demonstrate that multiple episodes of acute kidney injury contribute to the development and progression of kidney fibrosis. Although our understanding of kidney fibrosis has improved in the past two decades, we have limited therapeutic strategies to halt its progression. Myofibroblast differentiation and proliferation remain critical to the progression of kidney fibrosis. Although canonical Wnt signaling can trigger the activation of myofibroblasts in the kidney, mediators of Wnt inhibition in the resident progenitor cells are unclear. Recent studies demonstrate that the loss of a Krüppel-like factor 15 (KLF15), a kidney-enriched zinc-finger transcription factor, exacerbates kidney fibrosis in murine models. Here, we tested whether Klf15 mRNA and protein expression are reduced in late stages of fibrosis in mice that underwent unilateral ureteric obstruction, a model of progressive renal fibrosis. Knockdown of Klf15 in Foxd1-expressing cells (Foxd1-Cre Klf15fl/fl) increased extracellular matrix deposition and myofibroblast proliferation as compared to wildtype (Foxd1-Cre Klf15+/+) mice after three and seven days of ureteral obstruction. This was validated in mice receiving angiotensin II treatment for six weeks. In both these murine models, the increase in renal fibrosis was found in Foxd1-Cre Klf15 fl/fl mice and accompanied by the activation of Wnt/β-catenin signaling. Furthermore, knockdown of Klf15 in cultured mouse embryonic fibroblasts activated canonical Wnt/β-catenin signaling, increased profibrotic transcripts, and increased proliferation after treatment with a Wnt1 ligand. Conversely, the overexpression of KLF15 inhibited phospho-β-catenin (Ser552) expression in Wnt1-treated cells. Thus, KLF15 has a critical role in attenuating kidney fibrosis by inhibiting the canonical Wnt/β-catenin pathway., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)