Progression Of Renal Injury Research Articles

The progression of diabetes‐induced renal injury in Dahl salt‐sensitive rats

Diabetic nephropathy (DN) is the most common cause of chronic kidney failure in the US. However, little is known about the pathogenesis of DN because the lack of an appropriate rodent model. The aim of the present study was to determine whether the induction of diabetes in Dahl salt-sensitive (SS) rats would promote similar renal abnormalities as seen in patients with DN. Nine week-old SS rats were treated with either (1) vehicle or (2) streptozotocin (STZ, 50 mg/kg, i.p.) to induce diabetes and given insulin implants (2 U/day, s.c) to maintain plasma glucose between 300–400 mg/dL. Rats were fed a low salt diet to minimize the development of hypertension. At 18 weeks of age, protein excretion increased to 338±37 mg/day in STZ treated rats versus 54±6 mg/day in vehicle treated rats. Plasma blood urea nitrogen (BUN) levels were 67% higher in the STZ group compared to the vehicle group. Transforming growth factor beta and matrix metalloproteinase-2 protein levels were significantly elevated in the kidneys of the STZ group versus that seen in the vehicle group. STZ treated rats exhibited renal histological abnormalities typical of diabetes including mesangial expansion, glomeruloslcerosis, and interstitial fibrosis. These results indicate that SS rats treated with STZ develop progressive renal injury and display renal histopathological lesions characteristic to those seen in patients with DN. NIH grants HL36279 and HL29587

Programmed hypertension in rats treated with a NF-κB inhibitor during nephrogenesis: renal mechanisms

Suppression of the renin-angiotensin system (RAS) during murine lactation causes progressive renal injury, indicating a physiological action of angiotensin II on nephrogenesis. The nuclear factor NF-κB system is one of the main intracellular mediators of angiotensin II. We investigated whether inhibition of this system with pyrrolidine dithiocarbamate (PDTC) during rat nephrogenesis would lead to similar hypertension and renal injury as observed with RAS suppressors. Immediately after delivery, 32 Munich-Wistar dams, each nursing 6 male pups, were divided into 2 groups: C, untreated, and PDTC, receiving PDTC, 280 mg kg(-1) day(-1) orally, during 21 days. After weaning, the offspring were followed until 10 months of age without treatment. Adult rats that received neonatal PDTC exhibited stable hypertension and myocardial injury, without albuminuria. To gain additional insight into this process, the renal expression of RAS components and sodium transporters were determined by quantitative real-time PCR (qRT-PCR) at 3 and 10 months of life. Renal renin and angiotensinogen were upregulated at 3 and downregulated at 10 months of age, suggesting a role for early local RAS activation. Likewise, there was early upregulation of the proximal sodium/glucose and sodium/bicarbonate transporters, which abated later in life, suggesting that additional factors sustained hypertension in the long run. The conclusions drawn from the findings were as follows: (1) an intact NF-κB system during nephrogenesis may be essential to normal renal and cardiovascular function in adult life; (2) neonatal PDTC represents a new model of hypertension, lacking overt structural injury or functional impairment of the kidneys; and (3) hypertension in this model seems associated with early temporary activation of renal RAS and sodium transporters.

Renovascular disease, microcirculation, and the progression of renal injury: role of angiogenesis

Emerging evidence supports the pivotal role of renal microvascular disease as a determinant of tubulo-interstitial and glomerular fibrosis in chronic kidney disease. An intact microcirculation is vital to restore blood flow to the injured tissues, which is a crucial step to achieve a successful repair response. The purpose of this review is to discuss the impact and mechanisms of the functional and structural changes of the renal microvascular network, as well as the role of these changes in the progression and irreversibility of renal injury. Damage of the renal microcirculation and deterioration of the angiogenic response may constitute early steps in the complex pathways involved in progressive renal injury. There is limited but provocative evidence that stimulation of vascular proliferation and repair may stabilize renal function and slow the progression of renal disease. The feasibility of novel potential therapeutic interventions for stabilizing the renal microvasculature is also discussed. Targeted interventions to enhance endogenous renoprotective mechanisms focused on the microcirculation, such as cell-based therapy or the use of angiogenic cytokines have shown promising results in some experimental and clinical settings.

Renal injury in angiotensin II+l-NAME-induced hypertensive rats is independent of elevated blood pressure

The balance between angiotensin II (ANG II) and nitric oxide plays an important role in renal function and is thought to contribute to the progression of renal injury in experimental hypertension. In the present study, we investigated the extent of blood pressure (BP)-dependent and BP-independent pathways of renal injury following 2 wk of hypertension produced by intravenous infusion of ANG II (5 ng·kg⁻¹·min⁻¹)+N(ω)-nitro-l-arginine methyl ester (l-NAME; 1.4 μg·kg⁻¹·min⁻¹) in male Sprague-Dawley rats. An aortic balloon occluder was positioned between the renal arteries to maintain (24 h/day) BP to the left kidney (servo-controlled) at baseline levels, whereas the right kidney (uncontrolled) was chronically exposed to elevated BP. Over the 14-day experimental protocol, the average BP to uncontrolled kidneys (152.7 ± 1.8 mmHg) was significantly elevated compared with servo-controlled (113.0 ± 0.2 mmHg) kidneys and kidneys from sham rats (108.3 ± 0.1 mmHg). ANG II+l-NAME infusion led to renal injury that was focal in nature and mainly confined to the outer medulla. Despite the differences in BP between servo-controlled and uncontrolled kidneys, there was a similar ~3.5-fold increase in renal outer medullary tubular injury, ~2-fold increase in outer medullary interstitial fibrosis, ~2-fold increase in outer medullary macrophage infiltration, and a significant increase in renal oxidative stress, all of which are indicative of BP-independent mediated pathways. The results of this study have important implications regarding the pathogenesis of renal injury in various experimental models of hypertension and provide novel insights regarding the variable association observed between hypertension and renal injury in some human populations.

Angiotensinogen Expression Is Enhanced in the Progression of Glomerular Disease

Intrarenal renin-angiotensin system (RAS) activation plays a critical role in the development and progression of renal injury. In the kidney, all of the RAS components are present and intrarenal angiotensin II (Ang II) is formed by multiple independent mechanisms. Angiotensinogen (AGT) is the only known substrate for renin that is a rate-limiting enzyme of the RAS. Recently, enhanced intrarenal AGT levels have been shown to reflect the intrarenal RAS status in hypertension, chronic glomerular disease and diabetic nephropathy. In this review, we focus on AGT expression of the diseased glomeruli in the progression of glomerular disease. An anti-glomerular basement membrane nephritis rat model developed progressive proteinuria and glomerular crescent formation, accompanied by increased macrophage infiltration and glomerular expression of AGT and Ang II. The addition of Ang II type 1 receptor blocker to CC-chemokine recaptor 2 antagonist markedly attenuated the induction of macrophage infiltration, AGT and Ang II, and reduced glomerular crescent formation. Next, the levels of glomerular AGT expression and marker of reactive oxygen species in Zucker diabetic fatty (ZDF) obese rats were higher than those in ZDF lean rats. Hydrogen peroxide (H(2)O(2)) induced an increase in the AGT expression in primary rat mesangial cells. Furthermore, the H(2)O(2)-induced upregulation of AGT was inhibited by a mitogen-activated protein kinase kinase and a c-Jun N-terminal kinase inhibitor. These data suggest the potential contribution of enhanced AGT expression in glomeruli to the intrarenal RAS activation for the development of glomerular disease.

Pharmacological Management of Cardiorenal Syndromes

Cardiorenal syndromes are disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. The pharmacological management of Cardiorenal syndromes may be complicated by unanticipated or unintended effects of agents targeting one organ on the other. Hence, a thorough understanding of the pathophysiology of these disorders is paramount. The treatment of cardiovascular diseases and risk factors may affect renal function and modify the progression of renal injury. Likewise, management of renal disease and associated complications can influence heart function or influence cardiovascular risk. In this paper, an overview of pharmacological management of acute and chronic Cardiorenal Syndromes is presented, and the need for high-quality future studies in this field is highlighted.

Diverse Roles of TGF-β/Smads in Renal Fibrosis and Inflammation

TGF-β1 has been long considered as a key mediator in renal fibrosis and induces renal scarring largely by activating its downstream Smad signaling pathway. Interestingly, while mice overexpressing active TGF-β1 develop progressive renal injury, latent TGF-β1 plays a protective role in renal fibrosis and inflammation. Under disease conditions, Smad2 and Smad3 are highly activated, while Smad7 is degraded through the ubiquitin proteasome degradation mechanism. In addition to TGF-β1, many pathogenic mediators such as angiotensin II and advanced glycation end products can also activate the Smad pathway via both TGF-β-dependent and independent mechanisms. Smads interact with other signaling pathways, such as the MAPK and NF-κB pathways, to positively or negatively regulate renal inflammation and fibrosis. Studies from gene knockout mice demonstrate that TGF-β1 acts by stimulating its downstream Smads to diversely regulate kidney injury. In the context of renal fibrosis and inflammation, Smad3 is pathogenic, while Smad2 and Smad7 are protective. Smad4 exerts its diverse roles by transcriptionally enhancing Smad3-mediated renal fibrosis while inhibiting NF-κB-driven renal inflammation via a Smad7-dependent mechanism. Furthermore, we also demonstrated that TGF-β1 acts by stimulating Smad3 to positively or negatively regulate microRNAs to exert its fibrotic role in kidney disease. In conclusion, TGF-β/Smad signaling is a major pathway leading to kidney disease. Smad3 is a key mediator in renal fibrosis and inflammation, whereas Smad2 and Smad7 are renoprotective. Smad4 exerts its diverse role in promoting renal fibrosis while inhibiting inflammation. Thus, targeting the downstream TGF-β/Smad3 signaling pathway by gene transfer of either Smad7 or Smad3-dependent microRNAs may represent a specific and effective therapeutic strategy for kidney disease.

Effects of polyunsaturated fatty acid consumption in diabetic nephropathy

The complex metabolic, vascular and inflammatory perturbations that characterize diabetes mellitus often lead to progressive albuminuria, renal injury and dysfunction (diabetic nephropathy [DN]), and diabetes is the leading cause of end-stage renal disease in the US and Europe. Diet has an important role in cardiometabolic disorders and its potential influence on DN is of interest. Fatty acids are a major source of energy, but in excess, fatty acids (particularly saturated fatty acids) can induce lipotoxicity. Omega-3 polyunsaturated fatty acids (PUFAs) confer protection against cardiovascular disease-the major cause of death in patients with DN-by virtue of their antihyperlipidemic, antihypertensive, anti-inflammatory and other properties. Omega-6 PUFAs are also cardioprotective. However, a significant proportion of adults consume insufficient quantities of these essential nutrients. This Review describes the role of omega-3 and omega-6 PUFAs in nutrition and metabolism, with a focus on experimental, epidemiologic and clinical studies that have investigated their renoprotective effect in patients with diabetes. Results from a number of studies suggest, but do not firmly establish, that long-chain omega-3 PUFAs (found in fish oil) reduce albuminuria in the setting of DN. Intake of omega-6 fatty acids is associated with reduced albuminuria in experimental settings and in epidemiologic studies of DN. Although PUFAs do not seem to attenuate glomerular dysfunction, insufficient evidence exists to rule out such an effect. We feel that further research is needed into the potential of PUFA consumption and supplementation in DN.

Pathogenesis of Renal Injury in the Megabladder Mouse: A Genetic Model of Congenital Obstructive Nephropathy

Congenital obstructive nephropathy (CON) is the most common cause of chronic renal failure in children often leading to end-stage renal disease. The megabladder (mgb) mouse exhibits signs of urinary tract obstruction in utero resulting in the development of hydroureteronephrosis and progressive renal failure after birth. This study examined the development of progressive renal injury in homozygous mgb mice (mgb-/-). Renal ultrasound was used to stratify the disease state of mgb-/- mice, whereas surgical rescue was performed using vesicostomy. The progression of renal injury was characterized using a series of pathogenic markers including alpha smooth muscle isoactin (α-SMA), TGF-β1, connective tissue growth factor (CTGF), E-cadherin, F4/80, Wilm's tumor (WT)-1, and paired box gene (Pax) 2. This analysis indicated that mgb-/- mice are born with pathologic changes in kidney development that progressively worsen in direct correlation with the severity of hydronephrosis. The initiation and pattern of fibrotic development observed in mgb-/- kidneys appeared distinctive from previous animal models of obstruction. These observations suggest that the mgb mouse represents a unique small animal model for the study of CON.

Immune complex formation in IgA nephropathy: CD89 a ‘saint’ or a ‘sinner’?

New data suggest that a soluble form of the IgA receptor CD89 may be protective against development of progressive renal injury in IgA nephropathy (IgAN). Understanding how IgA triggers shedding of CD89 from myeloid cell surfaces could help clarify the process of immune complex formation in IgAN, and measurement of this soluble form of CD89 may in the future prove a useful prognostic indicator of end-stage renal disease in this common glomerulonephritis.

Central interactions of aldosterone and angiotensin II in aldosterone- and angiotensin II-induced hypertension

Many studies have implicated both angiotensin II (ANG II) and aldosterone (Aldo) in the pathogenesis of hypertension, the progression of renal injury, and cardiac remodeling after myocardial infarction. In several cases, ANG II and Aldo have been shown to have synergistic interactions in the periphery. In the present studies, we tested the hypothesis that ANG II and Aldo interact centrally in Aldo- and ANG II-induced hypertension in male rats. In rats with blood pressure (BP) and heart rate (HR) measured by DSI telemetry, intracerebroventricular (icv) infusions of the mineralocorticoid receptor (MR) antagonists spironolactone and RU28318 or the angiotensin type 1 receptor (AT1R) antagonist irbesartan significantly inhibited Aldo-induced hypertension. In ANG II-induced hypertension, icv infusion of RU28318 significantly reduced the increase in BP. Moreover, icv infusions of the reactive oxygen species (ROS) scavenger tempol or the NADPH oxidase inhibitor apocynin attenuated Aldo-induced hypertension. To confirm these effects of pharmacological antagonists, icv injections of either recombinant adeno-associated virus carrying siRNA silencers of AT1aR (AT1aR-siRNA) or MR (MR-siRNA) significantly attenuated the development of Aldo-induced hypertension. The immunohistochemical and Western blot analyses of AT1aR-siRNA- or MR-siRNA-injected rats showed a marked reduction in the expression of AT1R or MR in the paraventricular nucleus compared with scrambled siRNA rats. When animals from all studies underwent ganglionic blockade with hexamethonium, there was a smaller reduction in the fall of BP in animals receiving icv AT1R or MR antagonists. These results suggest that ANG II and Aldo interact in the brain in a mutually cooperative manner such that the functional integrity of both brain AT1R and MR are necessary for hypertension to be induced by either systemic ANG II or Aldo. The pressor effects produced by systemic ANG II or Aldo involve increased central ROS and sympathetic outflow.

A Transgenic Mouse Model for Studying the Role of the ParathyroidHormone‐Related Protein System in Renal Injury

Parathyroid hormone- (PTH-) related protein (PTHrP) and its receptor, the PTH1 receptor (PTH1R), are widely expressed in the kidney, where PTHrP exerts a modulatory action on renal function. PTHrP is known to be upregulated in several experimental nephropathies such as acute renal failure (ARF), obstructive nephropathy (ON) as well as diabetic nephropathy (DN). In this paper, we will discuss the functional consequences of chronic PTHrP overexpression in the damaged kidney using a transgenic mouse strain overexpressing PTHrP in the renal proximal tubule. In both ARF and ON, PTHrP displays proinflammatory and profibrogenic actions including the induction of epithelia to mesenquima transition. Moreover, PTHrP participates in the mechanisms of renal hypertrophy as well as proteinuria in experimental DN. Angiotensin II (Ang II), a critical factor in the progression of renal injury, appears to be, at least in part, responsible for endogenous PTHrP upregulation in these pathophysiological settings. These findings provide novel insights into the well-known protective effects of Ang II antagonists in renal diseases, paving the way for new therapeutic approaches.

Telmisartan prevents the progression of renal injury in daunorubicin rats with the alteration of angiotensin II and endothelin-1 receptor expression associated with its PPAR-γ agonist actions

Angiotensin II (Ang II) receptor blocker (ARB) suppresses the progression of kidney disease. However, there is limited information regarding the nephroprotective effect of ARB in daunorubicin (DNR)-induced nephrotoxicity in rats. We examined the alteration of the renal Ang II and endothelin-1 (ET-1) receptor expression and the action of telmisartan, an ARB, on DNR-induced nephrotoxicity. Sprague–Dawley rats were treated with a cumulative dose of 9 mg/kg DNR (i.v.). Telmisartan was administered orally every day for 6 weeks. DNR rats showed nephrotoxicity as evidenced by worsening renal function, which was evaluated by measuring protein in urine, levels of urea and creatinine in serum, lipid profiles, malondialdehyde level, and the glutathione peroxidase activity in kidney tissue. These changes were reversed by treatment with telmisartan, which resulted in significant improvement in renal function. Furthermore, telmisartan increased nephrin protein expression, and down-regulated renal expression of Ang II and its receptor Ang II type I. Renal protein expressions of ET-1 and its receptor ET-receptor type A were increased in DNR rats, and treatment with telmisartan attenuated these increased expressions. Telmisartan mediated a further increase in the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ). In addition, the expressions of cyclooxygenase-2 and cellular adhesion molecules were increased in DNR rats, which were attenuated by telmisartan. In conclusion, telmisartan has a protective effect on DNR-induced nephrotoxicity through Ang II and ET-1, with the alteration of their receptor expressions, which is associated with its anti-inflammatory and anti-oxidant effects at least in part through PPAR-γ agonistic actions.

High-calorie diet with moderate protein restriction prevents cachexia and ameliorates oxidative stress, inflammation and proteinuria in experimental chronic kidney disease

In earlier studies we found that a high-fat, high-energy diet (HFED) attenuates proteinuria, azotemia and lipid accumulation in the remnant kidney of rats subjected to 5/6 nephrectomy. This study was conducted to explore the mechanism of the salutary effect of HFED in association with moderate protein restriction in this model. The 5/6 nephrectomized male rats were randomized to receive regular rat chow (CRF group, n = 6) or HFED diet (CRF + HFED, n = 7) for 12 weeks. Sham-operated rats served as controls (n = 6). The CRF group exhibited azotemia, hypertension, proteinuria, diminished body weight, oxidative stress, glomerulosclerosis, tubulo-interstitial inflammation and upregulation of pro-oxidant [NAD(P)H oxidase], pro-inflammatory (NF-κB activation, increased MCP-1, lipoxygenase, ICAM-1, VCAM-1), pro-fibrotic (TGF-β, CTGF) and pro-apoptotic pathways (Bax, caspase-3) in the remnant kidney. Consumption of the HFED resulted in a 66% increment in lipid intake, 8% increment in carbohydrate intake and a 24% reduction in protein intake. The CRF + HFED group gained weight normally, had increments in leptin and adiponectin levels, and despite increments in plasma cholesterol and fatty acids, showed significant attenuation of oxidative stress, proteinuria and inflammation, and partial reversal of the remnant kidney upregulation of pro-oxidant, pro-inflammatory, pro-fibrotic and pro-apoptotic pathways. Consumption of high-energy diet in association with mild protein restriction results in suppression of upregulated pathways that drive progression of renal injury in the remnant kidney model. These findings may have relevance in the management of chronic kidney disease in humans.

A guideline for the inpatient care of children with pyelonephritis

BACKGROUND AND OBJECTIVES:Febrile urinary tract infections and pyelonephritis are common in children and frequently lead to hospitalization for management, especially in the child who appears toxic. The American Academy of Pediatrics (AAP) practice parameter on the diagnosis, treatment and evaluation of the initial urinary tract infection in febrile infants and young children provides experience and evidence-based guidelines for the practitioner caring for children between the ages of 2 months to 2 years. No established guideline exists for older children and the AAP guideline does not specifically focus on inpatient care.METHODS:We conducted a comprehensive review of recently published literature and practice guidelines to develop a consensus on the inpatient diagnosis and management of children with pyelonephritis.RESULTS:Eight recommendations are proposed for the diagnosis and management, including revised guidelines for the imaging studies postpyelonephritis on the basis of current best evidence.CONCLUSION:Proper diagnosis of pyelonephritis, timely initiation of appropriate therapy and identification of children at risk for renal injury will help to reduce immediate as well as long-term complications due to chronic kidney disease.

TLR9 and TLR4 are required for the development of autoimmunity and lupus nephritis in pristane nephropathy

Systemic lupus erythematosus is a common autoimmune disease, with kidney involvement a serious complication associated with poor prognosis. Humoral immune responses constitute the hallmark of disease, however T helper cells are required for the generation of autoantibodies, as well as the induction and progression of renal injury. Administration of pristane to genetically intact mice results in the development of hypergammaglobulinaemia with the production of lupus like autoantibodies and proliferative glomerulonephritis, with similarities to human lupus nephritis. TLRs are intricately linked to the development of autoimmunity and are involved in the development of lupus nephritis. We injected wild type, TLR9−/− and TLR4−/− mice with pristane and assessed cellular and humoral autoimmunity and renal injury, 8 months later. TLR9−/− mice demonstrated a predominant decrease in Th1 cytokine production which resulted in decreased anti-RNP antibody levels, while anti-dsDNA levels remained intact. Compared to wild type mice treated with pristane, functional and histological renal injury and glomerular immunoglobulin and complement deposition was decreased in TLR9−/− mice. TLR4−/− mice demonstrated a global decrease in both Th1, IFNγ, and Th17 associated IL-17A and IL-6 cytokine production. Autoantibody levels of anti-dsDNA and anti-RNP were both decreased. Renal injury was attenuated in TLR4−/− mice which demonstrated less glomerular immunoglobulin and complement deposition. These results demonstrate that both TLR9 and TLR4 are required for ‘full-blown’ autoimmunity and organ injury in experimental lupus induced by pristane.

Ang II enhances tubular cell Ets-1 expression and associated down stream signaling is mediated through AT1 receptors

Angiotensin II (Ang II) has been reported to play an important role in both the development and progression of renal injury. Many of the downstream effects of Ang II are mediated through the activation of nuclear factor-κB (NF-κB). In the present study, we evaluated the effect of Ang II on the activation of Ets-1 (a transcription factor) in tubular cells. In addition, we studied the expression of pro-inflammatory molecules transcribed by Ets-1 in response to Ang II. Mice receiving Ang II infusion showed enhanced renal cortical mRNA expression of Ets-1. Immunolabeling studies localized the expression of Ets-1 in distal tubular cells of mice receiving Ang II. However, this effect of Ang II was mitigated by telmisartan, an AT1-receptor blocker. Mice receiving Ang II infusion also showed increased tubular cell expression of macrophage chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1), and p21 when compared with control mice; nevertheless, this effect of Ang II was attenuated by telmisartan. In in vitro studies, Ang II enhanced mRNA expression of Ets-1 by MDCK cells. However, this effect of Ang II was inhibited by losartan, an AT1-receptor blocker. Losartan also inhibited Ang II-induced PAI-1 and p21 expression by MDCK cells. These findings indicate that Ang II-induced tubular cell expression Ets-1 and associated downstream signaling is mediated through AT1 receptors.

Correlation Between Tumor Necrosis Factor Alpha and Proteinuria in Type-2 Diabetic Patients

Introduction: Diabetic Nephropathy (DN) is the single most common cause of end stage renal disease (ESRD) in many countries. Inflammation is a potential factor in the development and progression of DN and recent data indicate that diabetes includes an inflammatory component which may contribute to diabetic complications. Methods: This study was conducted at Ain Shams University Hospital on 95 patients with type-2 diabetes mellitus complicated with retinopathy and fifteen age- and sex-matched healthy volunteers. Diabetic patients were divided into 4 groups according to the degree of proteinuria. Serum tumor necrosis factor-α (TNF-α), urine TNF-α and C-reactive protein (CRP) levels were measured in all subjects. Correlations between these inflammatory parameters and degree of proteinuria, duration of diabetes and degree of glycemic control were examined. Results: Levels of the three inflammatory parameters were significantly higher in diabetic patients when compared to control subjects, and they were positively correlated to urinary protein excretion. There was significant positive correlation between serum and urine TNF-α and duration of diabetes, as well as between serum TNF-α and glycemic control. Serum and urine TNF-α remained as independent predictors of urine protein excretion in diabetic patients with overt proteinuria after forward stepwise multiple regression analysis. Conclusion: Serum and urine TNF-α and CRP levels are significantly elevated in this group of diabetic patients, and correlate positively with severity of proteinuria. This suggests a significant role for TNF-α in the pathogenesis and progression of renal injury in diabetes mellitus. Keywards: Diabetic nephropathy; Proteinuria; Tumor necrosis factor-α

Increased Expression of Toll-Like Receptor 2 in Rat Diabetic Nephropathy

Background/Aims: Inflammation is implicated in the pathogenesis of diabetic nephropathy (DN). This study examined the role of Toll-like receptor 2 (TLR2) in the progression of renal injury in a model of rat DN. Methods: DN was induced by intravenous injection of streptozotocin and rats were sacrificed at week 2, 4 and 8. Functional and pathologic markers, inflammatory infiltration, expression of TLR2, MCP-1, MyD88, HSP70, HMGB1 and activation of NF-ĸB were assessed. The effects of glucose on the expression of TLR2 by renal tubular epithelial cells were also examined in vitro. Results: The expression of TLR2 mRNA and protein level was significantly upregulated in the kidneys of diabetic rats (p < 0.01), which was associated with increased renal expression of MyD88 and MCP-1, activation of NF-ĸB and infiltration of macrophages. The expression of HSP70 and HMGB1, endogenous ligands of TLRs, was also significantly upregulated in the kidneys of diabetic rats. In human renal biopsy of DN, there was prominent expression of TLR2 in both the glomeruli and tubulointerstitium. In vitro study showed that high glucose induced the expression of TLR2 mRNA by NRK-52E cells (p < 0.01). Conclusions: Enhanced renal expression of TLR2 is associated with inflammatory infiltration in DN.

TLR4 Promotes Fibrosis but Attenuates Tubular Damage in Progressive Renal Injury

Toll-like receptors (TLRs) can orchestrate an inflammatory response upon activation by pathogen-associated motifs and release of endogenous stress ligands during tissue injury. The kidney constitutively expresses most TLRs, including TLR4. The function of TLR4 during the inflammation, tubular atrophy, and fibrosis that accompany progressive renal injury is unknown. Here, we subjected wild-type (WT) and TLR4-deficient mice to unilateral ureteral obstruction and observed elevated levels of TLR4 mRNA in the kidney after obstruction. One day after unilateral ureteral obstruction, TLR4-deficient mice had fewer proliferating tubular epithelial cells and more tubular damage than WT mice; however, TLR4-deficient mice developed considerably less renal fibrosis despite decreased matrix metalloproteinase activity and without significant differences in myofibroblast accumulation. In vitro, TLR4-deficient primary tubular epithelial cells and myofibroblasts produced significantly less type I collagen mRNA after TGF-beta stimulation than WT cells. The reduced fibrosis in TLR4-deficient mice associated with an upregulation of Bambi, a negative regulator of TGF-beta signaling. In conclusion, TLR4 attenuates tubular damage but promotes renal fibrosis by modulating the susceptibility of renal cells to TGF-beta. These data suggest that TLR4 signaling may be a therapeutic target for the prevention of renal fibrosis.