Antifibrotic treatment and other new strategies for improving renal outcomes.
ABSTRACT: Diabetic nephropathy (DN) is clinically characterized by proteinuria and hypertension. Investigations suggest that matrix accumulation and inflammatory processes contribute to the pathological features of this progressive disease. This chapter reviews novel targeted approaches to the treatment of DN, with the goal of slowing the progression and improving renal function. Many studies support the use of agents that block the renin-angiotensin-aldosterone system in DN. Novel, oral agents that are promising in early clinical studies are agents such as pirfenidone and bardoxolone as they are associated with early improvement in renal function in patients with advanced diabetic kidney disease. Additionally, strategies that inhibit inflammatory cytokines, chemokines, adhesion molecules and mediators of the innate immune response may provide novel targets for the treatment of DN. Larger clinical studies are eagerly awaited to determine if new agents that specifically block kidney fibrosis and inflammation will delay, arrest and possibly reverse progressive renal failure.
Project description:The burden of diabetes mellitus is relentlessly increasing. Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) worldwide and a major cause of morbidity and mortality in patients with diabetes. The current standard therapy of diabetic nephropathy involves intensive treatment of hyperglycemia and strict blood pressure control, mainly via blockade of the renin-angiotensin system (RAS). Attention has been drawn to additional beneficial effects of oral hypoglycemic drugs and fibrates on other aspects of diabetic nephropathy. On the other hand, antiproteinuric effects of RAS combination therapy do not seem to enhance the prevention of renal disease progression, and it has been associated with an increased rate of serious adverse events. Novel agents, such as bardoxolone methyl, pentoxifylline, inhibitors of protein kinase C (PKC), sulodexide, pirfenidone, endothelin receptor antagonists, vitamin D supplements, and phosphate binders have been associated with controversial outcomes or significant side effects. Although new insights into the pathogenetic mechanisms have opened new horizons towards novel interventions, there is still a long way to go in the field of DN research. The aim of this review is to highlight the recent progress made in the field of diabetes management based on the existing evidence. The article also discusses novel targets of therapy, with a special focus on the major pathophysiologic mechanisms implicated in the initiation and progression of diabetic nephropathy.
Project description:Diabetic nephropathy is a leading cause of end-stage renal disease worldwide. The mainstay of treatment has been glycemic control and blood pressure lowering using agents blocking the renin-angiotensin system. Clinical trials are currently under way using novel agents for the treatment of patients with diabetic nephropathy. Promising agents emerging from some of the completed trials include pirfenidone and bardoxolone methyl, which have been shown in two recent randomized controlled trials in patients with diabetic nephropathy to result in an improved estimated glomerular filtration rate compared to placebo. Also, paricalcitol has been shown to decrease the urinary albumin-to-creatinine ratio, whereas sulodexide failed to do so in a large randomized double-blind placebo-controlled trial. Of note, pyridoxamine has also shown promise in the treatment of diabetic nephropathy if started early in the disease course. These preliminary trials have shown significant promise for managing patients with diabetic nephropathy, sparking active research in this field and providing the rationale for further clinical testing in long-term, hard-outcomes trials.
Project description:Despite advances in the treatment of diabetic nephropathy (DN), currently available therapies have not prevented the epidemic of progressive chronic kidney disease (CKD). The morbidity of CKD, and the inexorable increase in the prevalence of end-stage renal disease, demands more effective approaches to prevent and treat progressive CKD. We undertook next-generation sequencing in a rat model of diabetic nephropathy to study in depth the pathogenic alterations involved in DN with progressive CKD. We employed the obese, diabetic ZS rat, a model that develops diabetic nephropathy, characterized by progressive CKD, inflammation, and fibrosis, the hallmarks of human disease. We then used RNA-seq to examine the combined effects of renal cells and infiltrating inflammatory cells acting as a pathophysiological unit. The comprehensive systems biology analysis of progressive CKD revealed multiple interactions of altered genes that were integrated into morbid networks. These pathological gene assemblies lead to renal inflammation and promote apoptosis and cell cycle arrest in progressive CKD. Moreover, in what is clearly a major therapeutic challenge, multiple and redundant pathways were found to be linked to renal fibrosis, a major cause of kidney loss. We conclude that systems biology applied to progressive CKD in DN can be used to develop novel therapeutic strategies directed to restore critical anomalies in affected gene networks.
Project description:Inflammation and its consequent fibrosis are two main features of diabetic nephropathy (DN), but target therapy on these processes for DN remains yet ineffective. We report here that miR-29b is a novel therapeutic agent capable of inhibiting progressive renal inflammation and fibrosis in type 2 diabetes in db/db mice. Under diabetic conditions, miR-29b was largely downregulated in response to advanced glycation end (AGE) product, which was associated with upregulation of collagen matrix in mesangial cells via the transforming growth factor-? (TGF-?)/Smad3-dependent mechanism. These pathological changes were reversed by overexpressing miR-29b, but enhanced by knocking-down miR-29b. Similarly, loss of renal miR-29b was associated with progressive diabetic kidney injury, including microalbuminuria, renal fibrosis, and inflammation. Restored renal miR-29b by the ultrasound-based gene therapy was capable of attenuating diabetic kidney disease. Further studies revealed that inhibition of Sp1 expression, TGF-?/Smad3-dependent renal fibrosis, NF-?B-driven renal inflammation, and T-bet/Th1-mediated immune response may be mechanisms associated with miR-29b treatment in db/db mice. In conclusion, miR-29b may play a protective role in diabetic kidney disease and may have therapeutic potential for diabetic kidney complication.
Project description:BACKGROUND: Diabetic nephropathy (DN) is the leading cause of chronic kidney disease and is associated with excessive cardiovascular morbidity and mortality. The angiotensin converting enzyme inhibitor (ACEI) benazepril has been shown to slow the progression of chronic renal disease and have beneficial effects in patients with a combination of chronic renal disease and cardiovascular disease. Transforming growth factor-?(1) (TGF-?(1)) plays a central role in the pathogenesis and progression of DN. Integrin-linked kinase (ILK) can modulate TGF-?(1)-induced glomerular mesangial cell (GMC) injury, which is a prominent characteristic of renal pathology in kidney diseases. As an integrin cytoplasmic-binding protein, ILK regulates fibronectin (FN) matrix deposition and the actin cytoskeleton. Smooth muscle ?-actin (?-SMA) is involved in progressive renal dysfunction in both human and experimental renal disease. METHODS: To explore the mechanisms of benazepril's reno-protective effects, we examined the expression of TGF-?(1), ILK, and ?-SMA in GMC exposed to high glucose (HG) and in the kidneys of streptozotocin (STZ)-induced diabetic rats using real-time quantitative RT-PCR and western blot analysis. To elucidate the mechanism(s) of the effect of benazepril on GMC cellular processes, we assessed the effect of benazepril on Angiotensin II (Ang II) signalling pathways using western blot analysis. RESULTS: The expression of TGF-?(1), ILK, and ?-SMA increased significantly in the diabetic group compared with the control group. Benazepril treatment inhibited the expression of these genes in DN but failed to rescue the same levels in the control group. Similar results were found in GMC treated with HG or benazepril. Ang II increased ERK and Akt phosphorylation in the HG group, and benazepril could not completely block these responses, suggesting that other molecules might be involved in the progression of DN. Our findings suggest that benazepril decreases ILK and ?-SMA expression, at least in part, by affecting the interactions between Ang II and TGF-?(1). CONCLUSIONS: The findings described here support the hypothesis that the HG milieu of diabetes increases TGF-?(1) secretion, which increases the synthesis of ILK and ?-SMA that are involved in the progression of DN. This might be an important mechanism of the benazepril renal-protective function in the pathogenesis of DN.
Project description:Diabetic nephropathy (DN) remains incurable and is the main cause of end-stage renal disease. We approached the pathophysiology of DN with systems biology, and a comprehensive profile of renal transcripts was obtained with RNA-Seq in ZS (F1 hybrids of Zucker and spontaneously hypertensive heart failure) rats, a model of diabetic nephropathy. We included sham-operated lean control rats (LS), sham-operated diabetic (DS), and diabetic rats with induced renal ischemia (DI). Diabetic nephropathy in DI was accelerated by the single episode of renal ischemia. This progressive renal decline was associated with renal iron accumulation, although serum and urinary iron levels were far lower in DI than in LS. Furthermore, obese/diabetic ZS rats have severe dyslipidemia, a condition that has been linked to hepatic iron overload. Hence, we tested and found that the fatty acids oleic acid and palmitate stimulated iron accumulation in renal tubular cells in vitro. Renal mRNAs encoding several key proteins that promote iron accumulation were increased in DI. Moreover, renal mRNAs encoding the antioxidant proteins superoxide dismutase, catalase, and most of the glutathione synthetic system were suppressed, which would magnify the prooxidant effects of renal iron loads. Substantial renal iron loads occur in obese/diabetic rats. We propose that in diabetes, specific renal gene activation is partly responsible for iron accumulation. This state might be further aggravated by lipid-stimulated iron uptake. We suggest that progressive renal iron overload may further advance renal injury in obese/diabetic ZS rats.
Project description:OBJECTIVE:Increasing evidence shows that TGF-?1 is a key mediator in diabetic nephropathy (DN) and induces renal fibrosis positively by Smad3 but negatively by Smad7. However, treatment of DN by blocking the TGF-?/Smad pathway remains limited. The present study investigated the anti-fibrotic effect of a traditional Chinese medicine, Chaihuang-Yishen granule (CHYS), on DN. RESEARCH DESIGN AND METHODS:Protective role of CHYS in DN was examined in an accelerated type 1 DN induced by streptozotocin in uninephrectomized Wistar rats. CHYS, at a dose of 0.56 g/kg body weight, was administered by a daily gastric gavage for 20 weeks and the therapeutic effect and potential mechanisms of CHYS on diabetic kidney injury were examined. RESULTS:Treatment with CHYS attenuated diabetic kidney injury by significantly inhibiting 24-h proteinuria and progressive renal fibrosis including glomerulosclerotic index, tubulointerstitial fibrosis index, and upregulation of extracellular matrix (collagen I, IV, and fibronectin), despite the same levels of blood glucose. Further studies revealed that inhibition of renal fibrosis in CHYS-treated diabetic rats was associated with inhibition of TGF-?1/Smad3 signaling as demonstrated by upregulation of Smad7 but downregulation of TGF-?1, TGF-? receptors, activation of Smad3, and expression of miRNA-21. CONCLUSIONS:CHYS may be a therapeutic agent for DN. CHYS attenuates DN by blocking TGF-?/Smad3-mediated renal fibrosis.
Project description:BACKGROUND:Idiopathic pulmonary fibrosis (IPF) is characterized by a progressive and irreversible respiratory failure. Non-invasive markers of disease activity are essential for prognosis and evaluation of early response to anti-fibrotic treatments. OBJECTIVES:The aims of this study were to determine whether fluorodeoxyglucose ([18F]-FDG) lung uptake is reduced after initiation of pirfenidone or nintedanib and to assess its possible use as a prognostic factor. METHODS:[18F]-FDG PET/CT was performed in IPF patients and in a murine model of pulmonary fibrosis. PET/CTs were performed at day 8 and day 15 post-instillation of bleomycin in pirfenidone- or vehicule-treated mice. In IPF patients, PET-CT was performed before and 3?months after the initiation of pirfenidone or nintedanib. RESULTS:In bleomycin-treated mice, pirfenidone significantly reduced the [18F]-FDG uptake compared to vehicule-treated mice at day 15 (p?<?0.001), whereas no difference was observed at day 8 after bleomycin administration. In IPF patients, [18F]-FDG lung uptake before and after 3?months of treatment by nintedanib (n?=?11) or pirfenidone (n?=?14) showed no significant difference regardless the antifibrotic treatment. Moreover, no difference was noticed between patients with progressive or non-progressive disease at one year of follow up. CONCLUSIONS:Pirfenidone significantly reduces the lung [18F]-FDG uptake during the fibrotic phase in a mouse model of IPF. However, these preclinical data were not confirmed in IPF patients 3?months after the initiation of antifibrotic therapy. [18F]-FDG seems therefore not useful in clinical practice to assess the early response of IPF patients to nintedanib or pirfenidone.
Project description:PURPOSE:Renal fibrosis is a hallmark of progressive renal disease; however, current clinical tests are insufficient for assessing renal fibrosis. Here we evaluated the utility of quantitative magnetization transfer MRI in detecting renal fibrosis in a murine model of progressive diabetic nephropathy (DN). METHODS:The db/db eNOS-/- mice, a well-recognized model of progressive DN, and normal wild-type mice were imaged at 7T. The quantitative magnetization transfer data were collected in coronal plane using a 2D magnetization transfer prepared spoiled gradient echo sequence with a Gaussian-shaped presaturation pulse. Parameters were derived using a two-pool fitting model. A normal range of cortical pool size ratio (PSR) was defined as Mean±2SD of wild-type kidneys (N?=?20). The cortical regions whose PSR values exceeded this threshold (threshold PSR) were assessed. The correlations between the PSR-based and histological (collagen IV or picrosirius red stain) fibrosis measurements were evaluated. RESULTS:Compared with wild-type mice, moderate increases in mean PSR values and scattered clusters of high PSR region were observed in cortex of DN mouse kidneys. Abnormally high PSR regions (% area) that were detected by the threshold PSR were significantly increased in renal cortexes of DN mice. These regions progressively increased on aging and highly correlated with histological fibrosis measures, while the mean PSR values correlated much less. CONCLUSION:Renal fibrosis in DN can be assessed by the quantitative magnetization transfer MRI and threshold analysis. This technique may be used as a novel imaging biomarker for DN and other renal diseases.
Project description:The incidence of progressive kidney disease associated with diabetes continues to rise worldwide. Current standard therapy with angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers achieves only partial renoprotection, increasing the need for novel therapeutic approaches. Previous studies described B7-1 induction in podocytes of patients with proteinuria, including those with FSGS and type 2 diabetic nephropathy (DN). These findings sparked great excitement in the renal community, implying that abatacept, a costimulatory inhibitor that targets B7-1, could be a novel therapy for diabetic renal disease. Given previous concerns over the value of B7-1 immunostaining and the efficacy of abatacept in patients with recurrent FSGS after renal transplantation, we investigated B7-1 expression in human and experimental DN before embarking on clinical studies of the use of B7-1 targeting strategies to treat proteinuria in DN. Immunohistochemical analysis of kidney specimens using different antibodies revealed that B7-1 is not induced in podocytes of patients with DN, independent of disease stage, or BTBR ob/obmice, a model of type 2 diabetes. These results do not support the use of abatacept as a therapeutic strategy for targeting podocyte B7-1 for the prevention or treatment of DN.