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Diabetic nephropathy, a leading cause of end-stage renal disease, accounts for significant morbidity and mortality. It is characterized by microinflammation in the glomeruli and myofibroblast activation in the tubulointerstitium. Salvia miltiorrhiza Bunge, a traditional Chinese medicine, is shown to possess anti-inflammatory and anti-fibrotic properties, implying its renal-protective potential. This study investigates which type of component can reduce the damage caused by diabetic nephropathy in a single setting. The ethyl acetate (EtOAc) layer was demonstrated to provoke peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ activities in renal mesangial cells by dual luciferase reporter assay. In a high glucose (HG)-cultured mesangial cell model, the EtOAc layer substantially inhibited HG-induced elevations of interleukin-1β, transforming growth factor-β1 (TGF-β1), and fibronectin, whereas down-regulated PPAR-γ was restored. In addition, among the extracts of S. miltiorrhiza , the EtOAc layer effectively mitigated TGF-β1-stimulated myofibroblast activation. The EtOAc layer also showed a potent ability to attenuate renal hypertrophy, proteinuria, and fibrotic severity by repressing diabetes-induced proinflammatory factor, extracellular matrix accumulation, and PPAR-γ reduction in the STZ-induced diabetes mouse model. Our findings, both in vitro and in vivo, indicate the potential of the EtOAc layer from S. miltiorrhiza for future drug development targeting diabetic nephropathy.

Diabetic nephropathy (DN) is one of the major leading cause of kidney failure. To identify the progression of chronic kidney disease (CKD), renal function/fibrosis is playing a crucial role. Unfortunately, lack of sensitivities/specificities of available clinical biomarkers are key major issues for practical healthcare applications to identify the renal functions/fibrosis in the early stage of DN. Thus, there is an emerging approach such as therapeutic or diagnostic are highly desired to conquer the CKD at earlier stages. Herein, we applied and examined the application of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and diffusion weighted imaging (DWI) to identify the progression of fibrosis between wild type (WT) and miR29a transgenic (Tg) mice during streptozotocin (STZ)-induced diabetes. Further, we also validate the potential renoprotective role of miR29a to maintain the renal perfusion, volume, and function. In addition, Ktrans values of DCE-MRI and apparent diffusion coefficient (ADC) of DWI could significantly reflect the level of fibrosis between WT and Tg mice at identical conditions. As a result, we strongly believed that the present non-invasive MR imaging platforms have potential to serveas an important tool in research and clinical imaging for renal fibrosis in diabetes, and that microenvironmental changes could be identified by MR imaging acquisition prior to histological biopsy and diabetic podocyte dysfunction.

Diabetic nephropathy is a complication of diabetes that leads to end-stage kidney disease and is a major health burden worldwide. Prenylflavonoid compounds extracted from Macaranga tanarius (MTE) exhibit anti-inflammation, anti-oxidant, and anti-bacterial properties. However, the effects of these compounds on diabetic nephropathy remain unclear. The effects of MTE on diabetic nephropathy were investigated in vitro by using mouse renal mesangial cells and in vivo by using a db/db knockout mouse model. No overt alteration in proliferation was observed in mouse renal mesangial cells treated with 0–1 μg/mL MTE. Western blot analysis indicated that MTE dose-dependently attenuated the expression of fibronectin, α-smooth muscle actin, and collagen IV. Administration of MTE ameliorated renal albumin loss in db/db mice. Immunohistochemical staining revealed that MTE mitigated diabetes-induced fibronectin and collagen IV expression. Periodic acid–Schiff (PAS) and trichrome staining also showed that administration of MTE reduced the renal fibrosis phenomenon. MTE significantly ameliorated diabetes-induced nephropathy. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) can cause inflammation and fibrosis, in addition to being the main complication of diabetes. Among many factors, epigenetic alterations in aberrant histone modifications play a key role in causing DKD. In this study, the mechanism of GSK-J4, a histone demethylase KDM6A inhibitor, was evaluated in streptozotocin-induced diabetic mice. It was confirmed that GSK-J4, via dickkopf-1 (DKK1) modulation, could significantly reduce proteinuria and glomerulosclerosis in diabetic mice. The mRNA accumulation levels of DKK1, TGF-β1, fibronectin, and collagen IV were significantly elevated in diabetic mice. In contrast, the mRNA accumulations of those genes were significantly reduced in diabetic mice treated with GSK-J4 compared to those in diabetic mice, relatively speaking. The protein accumulation levels of fibronectin and collagen IV were significantly elevated in diabetic mice. Furthermore, GSK-J4 attenuated the high glucose-induced expression of profibrotic factors in mesangial cells via DKK1. In conclusion, our study provides a novel strategy to eliminate fibrosis in the kidneys of DKD mice. Using GSK-J4 reduces DKK1 expression, thereby ameliorating renal insufficiency, glomerulosclerosis morphological abnormalities, inflammation, and fibrosis in diabetic mice. [ABSTRACT FROM AUTHOR]

Intensive fibrosis in the glomerular microenvironment is a prominent feature of diabetic nephropathy. Cannabinoid receptor 1 (CB1R) reportedly mediates diabetes-induced renal injury. However, studies on the molecular events underlying CB1R promotion of renal dysfunction are limited. This study is undertaken to investigate whether CB1R signaling via Ras or PPARγ pathway regulates mesangial fibrosis in diabetic kidneys. In streptozotocin-induced diabetic rats, hyperglycemia induced glomerular hypertrophy and fibrosis in association with increased IL-1β, fibronectin, and CB1R expressions and reduced PPARγ2 signaling. CB1R transgenic mice gained kidney weight, and renal glomeruli strongly displayed IL-1β and fibrotic matrices. Disruption of CB1R by antisense oligonucleotides or inverse agonist AM251 restored PPARγ2 signaling and reduced the promotional effects of hyperglycemia on the expression of fibrogenic transcription factor c-Jun, inflammation regulator SOCS3, proinflammatory cytokines, and accumulation of fibrotic matrix. PPARγ agonist rosiglitazone reduced the hyperglycemia-mediated enhancement of CB1R signaling, inflammation, and glomerular fibrosis in diabetic animals. In vitro, CB1R antagonism restored PPARγ2 action and reduced the promotional effects of high glucose on Ras, ERK, c-Jun, SOCS3 signaling, IL-1β, and fibronectin expression in renal mesangial cells. Activation of PPARγ2 reduced the high glucose-induced CB1R expression in mesangial cells. Taken together, CB1R signaling contributes to the hyperglycemia disturbance of PPARγ2 signaling and increases inflammatory cytokine secretion and fibrotic matrix deposition in renal glomeruli. CB1R mediates the hyperglycemia-induced inflammation and fibrosis in mesangial cells by regulating Ras, ERK, and PPARγ2 signaling. CB1R blockade has a therapeutic potential to reduce the deleterious actions of hyperglycemia on renal glomerular integrity. Key message: [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end-stage renal disease. The natural history of DKD includes glomerular hyperfiltration, progressive albuminuria, declining estimated glomerular filtration rate, and, ultimately, kidney failure. It is known that DKD is associated with metabolic changes caused by hyperglycemia, resulting in glomerular hypertrophy, glomerulosclerosis, and tubulointerstitial inflammation and fibrosis. Hyperglycemia is also known to cause programmed epigenetic modification. However, the detailed mechanisms involved in the onset and progression of DKD remain elusive. In this review, we discuss recent advances regarding the pathogenic mechanisms involved in DKD. [ABSTRACT FROM AUTHOR]