Kidney atrophy vs hypertrophy in diabetes: which cells are involved?

One of the first structural changes in diabetic nephropathy (DN) is the renal enlargement. These changes resulted in renal hypertrophy in both glomerular and tubular cells. Shrink in the kidney size, which described as kidney atrophy resulted from the loss of nephrons or abnormal nephron function and lead to loss of the kidney function. On the other hand, increase in kidney size, which described as hypertrophy resulted from increase in proximal tubular epithelial and glomerular cells size. However overtime, tubular atrophy and tubulointerstitial fibrosis occurs as subsequent changes in tubular cell hypertrophy, which is associated with the infiltration of fibroblast cells into the tubulointerstitial space. The rate of deterioration of kidney function shows a strong correlation with the degree of tubulointerstitial fibrosis. A consequence of long-standing diabetes/hyperglycemia may lead to major changes in renal structure that occur but not specific only to nephropathy. Identifying type of cells that involves in renal atrophy and hypertrophy may help to find a therapeutic target to treat diabetic nephropathy. In summary, the early changes in diabetic kidney are mainly includes the increase in tubular basement membrane thickening which lead to renal hypertrophy. On the other hand, only renal tubule is subjected to apoptosis, which is one of the characteristic morphologic changes in diabetic kidney to form tubular atrophy at the late stage of diabetes.     

Role of TGF-β in chronic kidney disease: an integration of tubular,glomerular and vascular effects

Transforming growth factor beta (TGF-β) has been recognized as an important mediator in the genesis of chronic kidney diseases (CKD), which are characterized by the accumulation of extracellular matrix (ECM) components in the glomeruli (glomerular fibrosis, glomerulosclerosis) and the tubular interstitium (tubulointerstitial fibrosis). Glomerulosclerosis is a major cause of glomerular filtration rate reduction in CKD and all three major glomerular cell types (podocytes or visceral epithelial cells, mesangial cells and endothelial cells) participate in the fibrotic process. TGF-β induces (1) podocytopenia caused by podocyte apoptosis and detachment from the glomerular basement membrane; (2) mesangial expansion caused by mesangial cell hypertrophy, proliferation (and eventually apoptosis) and ECM synthesis; (3) endothelial to mesenchymal transition giving rise to glomerular myofibroblasts, a major source of ECM. TGF-β has been shown to mediate several key tubular pathological events during CKD progression, namely fibroblast proliferation, epithelial to mesenchymal transition, tubular and fibroblast ECM production and epithelial cell death leading to tubular cell deletion and interstitial fibrosis. In this review, we re-examine the mechanisms involved in glomerulosclerosis and tubulointerstitial fibrosis and the way that TGF-β participates in renal fibrosis, renal parenchyma degeneration and loss of function associated with CKD.     

The proximal tubule in the pathophysiology of the diabetic kidney

Diabetic nephropathy is a leading cause of end-stage renal disease. A better understanding of the molecular mechanism involved in the early changes of the diabetic kidney may permit the development of new strategies to prevent diabetic nephropathy. This review focuses on the proximal tubule in the early diabetic kidney, particularly on its exposure and response to high glucose levels, albuminuria, and other factors in the diabetic glomerular filtrate, the hyperreabsorption of glucose, the unique molecular signature of the tubular growth phenotype, including aspects of senescence, and the resulting cellular and functional consequences. The latter includes the local release of proinflammatory chemokines and changes in proximal tubular salt and fluid reabsorption, which form the basis for the strong tubular control of glomerular filtration in the early diabetic kidney, including glomerular hyperfiltration and odd responses like the salt paradox. Importantly, these early proximal tubular changes can set the stage for oxidative stress, inflammation, hypoxia, and tubulointerstitial fibrosis, and thereby for the progression of diabetic renal disease.     

Acute Kidney Injury Urinary Biomarker Time-Courses

Factors which modify the excretion profiles of acute kidney injury biomarkers are difficult to measure. To facilitate biomarker choice and interpretation we modelled key modifying factors: extent of hyperfiltration or reduced glomerular filtration rate, structural damage, and reduced nephron number. The time-courses of pre-formed, induced (upregulated), and filtered biomarker concentrations were modelled in single nephrons, then combined to construct three multiple-nephron models: a healthy kidney with normal nephron number, a non-diabetic hyperfiltering kidney with reduced nephron number but maintained total glomerular filtration rate, and a chronic kidney disease kidney with reduced nephron number and reduced glomerular filtration rate. Time-courses for each model were derived for acute kidney injury scenarios of structural damage and/or reduced nephron number. The model predicted that pre-formed biomarkers would respond quickest to injury with a brief period of elevation, which would be easily missed in clinical scenarios. Induced biomarker time-courses would be influenced by biomarker-specific physiology and the balance between insult severity (which increased single nephron excretion), the number of remaining nephrons (reduced total excretion), and the extent of glomerular filtration rate reduction (increased concentration). Filtered biomarkers have the longest time-course because plasma levels increased following glomerular filtration rate decrease. Peak concentration and profile depended on the extent of damage to the reabsorption mechanism and recovery rate. Rapid recovery may be detected through a rapid reduction in urinary concentration. For all biomarkers, impaired hyperfiltration substantially increased concentration, especially with chronic kidney disease. For clinical validation of these model-derived predictions the clinical biomarker of choice will depend on timing in relation to renal insult and interpretation will require the pre-insult nephron number (renal mass) and detection of hyperfiltration.     

CDC20 inhibition alleviates fibrotic response of renal tubular epithelial cells and fibroblasts by regulating nuclear translocation of β-catenin

Fibrosis is a common pathological phenomenon in progressive kidney disease leading to eventual loss of kidney function. Previous studies demonstrated that CDC20 plays a role in cancers by regulating epithelial-mesenchymal transition (EMT) and the infiltration of fibroblasts, suggesting the potential of CDC20 in regulating fibrotic response. However, the role of CDC20 in renal fibrosis is yet unclear. Herein, we reported that renal CDC20 was remarkably upregulated in renal tubular epithelial cells and fibroblasts in chronic kidney disease (CKD) patients, which was in line with a positive correlation with the severity of kidney fibrosis. In mice with unilateral urinary obstruction, CDC20 was also strikingly enhanced, and treatment with Apcin, an inhibitor of CDC20, ameliorated kidney fibrosis. Consistently, the pharmacological inhibition of CDC20 in mouse proximal tubular epithelial cells and rat fibroblasts attenuated TGF-β1-induced fibrotic responses, while overexpression of CDC20 aggravated such responses. Additional studies revealed that CDC20 induces nuclear translocation of β-catenin, which in turn initiates and promotes the pathological process of fibrosis in CKD. Thus, enhanced CDC20 in renal tubular cells and fibroblasts promotes renal fibrosis by activating β-catenin, and CDC20 inhibition may serve as a promising strategy for the prevention and treatment of renal fibrosis.     

Identification of a microRNA signature in renal fibrosis: role of miR-21

Renal fibrosis is a final stage of many forms of kidney disease and leads to impairment of kidney function. The molecular pathogenesis of renal fibrosis is currently not well-understood. microRNAs (miRNAs) are important players in initiation and progression of many pathologic processes including diabetes, cancer, and cardiovascular disease. However, the role of miRNAs in kidney injury and repair is not well-characterized. In the present study, we found a unique miRNA signature associated with unilateral ureteral obstruction (UUO)-induced renal fibrosis. We found altered expression in UUO kidneys of miRNAs that have been shown to be responsive to stimulation by transforming growth factor (TGF)-β1 or TNF-α. Among these miRNAs, miR-21 demonstrated the greatest increase in UUO kidneys. The enhanced expression of miR-21 was located mainly in distal tubular epithelial cells. miR-21 expression was upregulated in response to treatment with TGF-β1 or TNF-α in human renal tubular epithelial cells in vitro. Furthermore, we found that blocking miR-21 in vivo attenuated UUO-induced renal fibrosis, presumably through diminishing the expression of profibrotic proteins and reducing infiltration of inflammatory macrophages in UUO kidneys. Our data suggest that targeting specific miRNAs could be a novel therapeutic approach to treat renal fibrosis.     

Primary kidney growth and its consequences at the onset of diabetes mellitus

Summary. Diabetes mellitus is a primary contributor to progressive kidney dysfunction leading to end-stage renal disease (ESRD). In the early phase of diabetes, prior to the onset of further complications, both kidney size and glomerular filtration rate (GFR) increase. Glomerular hyperfiltration is considered a risk factor for downstream complications and progression to ESRD. Abnormalities in vascular control have been purported to account for the glomerular hyperfiltration in early diabetes. In this review we discuss a tubulo-centric concept in which tubular growth and subsequent hyper-reabsorption contribute to the onset of glomerular hyperfiltration that demarks the early stage of diabetes. Kidney growth, in this concept, is no longer relegated to a compensatory response to hyperfiltration, but rather plays a primary and active role in its genesis and progression. As such, components of kidney growth, such as the polyamines, may provide a means of early detection of diabetic kidney dysfunction and more effective therapeutic intervention.     

ICAM-1 interactions in the renal interstitium: a novel activator of fibroblasts during nephritis.

Chronic renal diseases often degenerate towards end-stage failure, requiring replacement renal therapy. The progressive decline of such diseases is a highly complex, multi-factorial process, which is poorly understood. Indeed, not all chronic conditions take on a progressive course, some may recover to regain normal function, while others may remain functionally impaired yet stable. The structural features of progressive decline, however, show common histological features, despite the diverse nature of the primary injury. These aberrant structural alterations are characterised essentially by a dramatic expansion of the tubulointerstitium, with accompanying tubular atrophy, resulting from interstitial fibrosis. These changes are thought to be a uniform response to prolonged inflammation which may originate in the glomerulus, the vasculature or the interstitial space (Strutz et al., 1995). A histomorphometric analysis of renal diseases, initially performed by Risdon et al. (1968), and supported by Bohle et al. (1987) and others (Eknoyan et al., 1990), revealed that the severity of abnormal glomerular pathology did not always correlate directly with impaired renal function. The extent of interstitial inflammation and the degree of interstitial fibrosis, however, were both shown to be more accurate predictors of renal function (Bohle et al., 1992). Furthermore there was a high probability of irreversible functional decline, in the presence of interstitial fibrotic lesions and tubular atrophy. Interstitial fibrosis is therefore considered an important histological marker for end stage renal failure, and is believed to be functionally more significant than primary changes within the glomerulus. In most tissues, resident fibroblasts are believed to be the cells principally responsible for the synthesis and breakdown of extracellular matrix (ECM) within connective tissues. Indeed in fibrotic diseases of lung and skin, the resident fibroblast has been identified as the most important cell responsible for the abnormal deposition of ECM components during the disease process (Phan et al., 1985). In the kidney, there are probably several sources of matrix components during fibrosis including tubular epithelial cells, inflammatory macrophages (Vaage and Linbland, 1990) as well as interstitial fibroblasts. Although the precise cellular source of the bulk of this matrix requires clarification, there is mounting evidence supporting a significant contribution from resident or infiltrating fibroblasts (Rodemann and Muller, 1990, 1991a,b; Strutz and Muller, 1995).     

Pressure diuresis mechanism in the control of renal function and arterial pressure

Precise knowledge of the interrelationships between arterial pressure and urinary excretion of sodium and water is crucial to understanding the long-term control of arterial pressure. Although increases in renal perfusion pressure have been known for more than 35 years to inhibit tubular reabsorption, the mechanism of this pressure diuresis response, the humoral or physical factors involved, and even the nephron segments in which the changes in tubular function occur remain relatively unknown. This review focuses on the experimental evidence that supports current hypotheses concerning the mechanism of pressure diuresis. Specifically, it examines the possibility that pressure diuresis is caused by a small increase in glomerular filtration rate, alterations in the humoral or physical factors regulating proximal tubular reabsorption, and/or inhibition of tubular reabsorption in deep nephrons secondary to changes in hemodynamics in juxtamedullary nephrons. The concept originally proposed that the kidney serves as the dominant long-term controller of arterial pressure is largely based on the assumptions that the pressure diuresis phenomenon exists and that it occurs via a nonadaptive mechanism. It has been proposed that hypertension can develop only if the relationship between arterial pressure and sodium excretion is shifted toward higher pressures. The remainder of this review examines recent evidence indicating that an abnormality in the pressure natriuresis relationship may be associated with the development of hypertension in humans and in the genetic rat models of the disease.     

Pre-emptive pharmacological inhibition of fatty acid–binding protein 4 attenuates kidney fibrosis by reprogramming tubular lipid metabolism

Kidney fibrosis is a hallmark of chronic kidney disease (CKD) progression that is caused by tubular injury and dysregulated lipid metabolism. Genetic abolition fatty acid-binding protein 4 (FABP4), a key lipid transporter, has been reported to suppress kidney interstitial fibrosis. However, the role and underlying mechanism of chemical inhibition of FABP4 in fibrotic kidney have not been well-documented. Here, we examined preemptive the effect of a FABP4 inhibitor, BMS309403, on lipid metabolism of tubular epithelial cells (TECs) and progression of kidney fibrosis. The expression of FABP4 was significantly elevated, concomitated with the accumulation of lipid droplets in TECs during kidney fibrosis. Treatment with BMS309403 alleviated lipid deposition of TECs, as well as interstitial fibrotic responses both in unilateral ureteral obstruction (UUO)-engaged mice and TGF-β-induced TECs. Moreover, BMS309403 administration enhanced fatty acid oxidation (FAO) in TECs by regulating peroxisome proliferator-activated receptor γ (PPARγ) and restoring FAO-related enzyme activities; In addition, BMS309403 markedly reduced cell lipotoxicity, such as endoplasmic reticulum (ER) stress and apoptosis in fibrotic kidney. Taken together, our results suggest that preemptive pharmacological inhibition of FABP4 by BMS309403 rebalances abnormal lipid metabolism in TECs and attenuates the progression of kidney fibrosis, thus may hold therapeutic potential for the treatment of fibrotic kidney diseases.Subject terms: Metabolism, Chronic kidney disease     

TGF-β1 → SMAD/p53/USF2 → PAI-1 transcriptional axis in ureteral obstruction-induced renal fibrosis

Chronic kidney disease constitutes an increasing medical burden affecting 26 million people in the United States alone. Diabetes, hypertension, ischemia, acute injury, and urological obstruction contribute to renal fibrosis, a common pathological hallmark of chronic kidney disease. Regardless of etiology, elevated TGF-β1 levels are causatively linked to the activation of profibrotic signaling pathways initiated by angiotensin, glucose, and oxidative stress. Unilateral ureteral obstruction (UUO) is a useful and accessible model to identify mechanisms underlying the progression of renal fibrosis. Plasminogen activator inhibitor-1 (PAI-1), a major effector and downstream target of TGF-β1 in the progression of several clinically important fibrotic disorders, is highly up-regulated in UUO and causatively linked to disease severity. SMAD and non-SMAD pathways (pp60^c-src, epidermal growth factor receptor [EGFR], mitogen-activated protein kinase, p53) are required for PAI-1 induction by TGF-β1. SMAD2/3, pp60^c-src, EGFR, and p53 activation are each increased in the obstructed kidney. This review summarizes the molecular basis and translational significance of TGF-β1-stimulated PAI-1 expression in the progression of kidney disease induced by ureteral obstruction. Mechanisms discussed here appear to be operative in other renal fibrotic disorders and are relevant to the global issue of tissue fibrosis, regardless of organ site.     

Molecular Markers of Tubulointerstitial Fibrosis and Tubular Cell Damage in Patients with Chronic Kidney Disease

In chronic kidney disease (CKD), progressive nephron loss causes glomerular sclerosis, as well as tubulointerstitial fibrosis and progressive tubular injury. In this study, we aimed to identify molecular changes that reflected the histopathological progression of renal tubulointerstitial fibrosis and tubular cell damage. A discovery set of renal biopsies were obtained from 48 patients with histopathologically confirmed CKD, and gene expression profiles were determined by microarray analysis. The results indicated that hepatitis A virus cellular receptor 1 (also known as Kidney Injury Molecule-1, KIM-1), lipocalin 2 (also known as neutrophil gelatinase-associated lipocalin, NGAL), SRY-box 9, WAP four-disulfide core domain 2, and NK6 homeobox 2 were differentially expressed in CKD. Their expression levels correlated with the extent of tubulointerstitial fibrosis and tubular cell injury, determined by histopathological examination. The expression of these 5 genes was also increased as kidney damage progressed in a rodent unilateral ureteral obstruction model of CKD. We calculated a molecular score using the microarray gene expression profiles of the biopsy specimens. The composite area under the receiver operating characteristics curve plotted using this molecular score showed a high accuracy for diagnosing tubulointerstitial fibrosis and tubular cell damage. The robust sensitivity of this score was confirmed in a validation set of 5 individuals with CKD. These findings identified novel molecular markers with the potential to contribute to the detection of tubular cell damage and tubulointerstitial fibrosis in the kidney.     

Increased Expression of Intranuclear Matrix Metalloproteinase 9 in Atrophic Renal Tubules Is Associated with Renal Fibrosis

Background

Reduced turnover of extracellular matrix has a role in renal fibrosis. Matrix metalloproteinases (MMPs) is associated with many glomerular diseases, but the histological association of MMPs and human renal fibrosis is unclear.

Methods

This is a retrospective study. Institutional Review Board approval was obtained for the review of patients’ medical records, data analysis and pathological specimens staining with waiver of informed consents. Specimens of forty-six patients were examined by immunohistochemical stain of MMP-9 in nephrectomized kidneys, and the association of renal expression of MMP-9 and renal fibrosis was determined. MMP-9 expression in individual renal components and fibrosis was graded as high or low based on MMP-9 staining and fibrotic scores.

Results

Patients with high interstitial fibrosis scores (IFS) and glomerular fibrosis scores (GFS) had significantly higher serum creatinine, lower estimated glomerular filtration rate (eGFR), and were more likely to have chronic kidney disease (CKD) and urothelial cell carcinoma. Univariate analysis showed that IFS and GFS were negatively associated with normal and atrophic tubular cytoplasmic MMP-9 expression and IFS was positively correlated with atrophic tubular nuclear MMP-9 expression. Multivariate stepwise regression indicated that MMP-9 expression in atrophic tubular nuclei (r = 0.4, p = 0.002) was an independent predictor of IFS, and that MMP-9 expression in normal tubular cytoplasm (r = −0.465, p<0.001) was an independent predictor of GFS.

Conclusions

Interstitial fibrosis correlated with MMP-9 expression in the atrophic tubular nuclei. Our results indicate that renal fibrosis is associated with a decline of MMP-9 expression in the cytoplasm of normal tubular cells and increased expression of MMP-9 in the nuclei of tubular atrophic renal tubules.     

Protease‐activated receptor‐1 contributes to renal injury and interstitial fibrosis during chronic obstructive nephropathy

End‐stage renal disease, the final stage of all chronic kidney disorders, is associated with renal fibrosis and inevitably leads to renal failure and death. Transition of tubular epithelial cells (TECs) into mesenchymal fibroblasts constitutes a proposed mechanism underlying the progression of renal fibrosis and here we assessed whether protease‐activated receptor (PAR)‐1, which recently emerged as an inducer of epithelial‐to‐mesenchymal transition (EMT), aggravates renal fibrosis. We show that PAR‐1 activation on TECs reduces the expression of epithelial markers and simultaneously induces mesenchymal marker expression reminiscent of EMT. We next show that kidney damage was reduced in PAR‐1‐deficient mice during unilateral ureter obstruction (UUO) and that PAR‐1‐deficient mice develop a diminished fibrotic response. Importantly, however, we did hardly observe any signs of mesenchymal transition in both wild‐type and PAR‐1‐deficient mice suggesting that diminished fibrosis in PAR‐1‐deficient mice is not due to reduced EMT. Instead, the accumulation of macrophages and fibroblasts was significantly reduced in PAR‐1‐deficient animals which were accompanied by diminished production of MCP‐1 and TGF‐β. Overall, we thus show that PAR‐1 drives EMT of TECs in vitro and aggravates UUO‐induced renal fibrosis although this is likely due to PAR‐1‐dependent pro‐fibrotic cytokine production rather than EMT.     

Research progress of endothelial‐mesenchymal transition in diabetic kidney disease

Renal fibrosis is an important pathological feature of diabetic kidney disease (DKD), manifested as tubular interstitial fibrosis, tubular atrophy, glomerulosclerosis and damage to the normal structure of the kidney. Renal fibrosis can eventually develop into renal failure. A better understanding of renal fibrosis in DKD is needed due to clinical limitations of current anti‐fibrotic drugs in terms of effectiveness, cost‐effectiveness and side effects. Fibrosis is characterized by local excessive deposition of extracellular matrix, which is derived from activated myofibroblasts to increase its production or specific tissue inhibitors of metalloproteinases to reduce its degradation. In recent years, endothelial‐mesenchymal transition (EndMT) has gradually integrated into the pathogenesis of fibrosis. In animal models of diabetic kidney disease, it has been found that EndMT is involved in the formation of renal fibrosis and multiple signalling pathways such as TGF‐β signalling pathway, Wnt signalling pathway and non‐coding RNA network participate in the regulation of EndMT during fibrosis. Here, we mainly review EndMT regulation and targeted therapy of renal fibrosis in DKD.     

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.     

Nicotinamide reduces renal interstitial fibrosis by suppressing tubular injury and inflammation

Renal interstitial fibrosis is a common pathological feature in progressive kidney diseases currently lacking effective treatment. Nicotinamide (NAM), a member of water‐soluble vitamin B family, was recently suggested to have a therapeutic potential for acute kidney injury (AKI) in mice and humans. The effect of NAM on chronic kidney pathologies, including renal fibrosis, is unknown. Here we have tested the effects of NAM on renal interstitial fibrosis using in vivo and in vitro models. In vivo, unilateral urethral obstruction (UUO) induced renal interstitial fibrosis as indicated Masson trichrome staining and expression of pro‐fibrotic proteins, which was inhibited by NAM. In UUO, NAM suppressed tubular atrophy and apoptosis. In addition, NAM suppressed UUO‐associated T cell and macrophage infiltration and induction of pro‐inflammatory cytokines, such as TNF‐α and IL‐1β. In cultured mouse proximal tubule cells, NAM blocked TGF–β‐induced expression of fibrotic proteins, while it marginally suppressed the morphological changes induced by TGF‐β. NAM also suppressed the expression of pro‐inflammatory cytokines (eg MCP‐1 and IL‐1β) during TGF‐β treatment of these cells. Collectively, the results demonstrate an anti‐fibrotic effect of NAM in kidneys, which may involve the suppression of tubular injury and inflammation.     

Regression of Glomerular and Tubulointerstitial Injuries by Dietary Salt Reduction with Combination Therapy of Angiotensin II Receptor Blocker and Calcium Channel Blocker in Dahl Salt-Sensitive Rats

A growing body of evidence indicates that renal tissue injuries are reversible. We investigated whether dietary salt reduction with the combination therapy of angiotensin II type 1 receptor blocker (ARB) plus calcium channel blocker (CCB) reverses renal tissue injury in Dahl salt-sensitive (DSS) hypertensive rats. DSS rats were fed a high-salt diet (HS; 4% NaCl) for 4 weeks. Then, DSS rats were given one of the following for 10 weeks: HS diet; normal-salt diet (NS; 0.5% NaCl), NS + an ARB (olmesartan, 10 mg/kg/day), NS + a CCB (azelnidipine, 3 mg/kg/day), NS + olmesartan + azelnidipine or NS + hydralazine (50 mg/kg/day). Four weeks of treatment with HS diet induced hypertension, proteinuria, glomerular sclerosis and hypertrophy, glomerular podocyte injury, and tubulointerstitial fibrosis in DSS rats. A continued HS diet progressed hypertension, proteinuria and renal tissue injury, which was associated with inflammatory cell infiltration and increased proinflammatory cytokine mRNA levels, NADPH oxidase activity and NADPH oxidase-dependent superoxide production in the kidney. In contrast, switching to NS halted the progression of hypertension, renal glomerular and tubular injuries. Dietary salt reduction with ARB or with CCB treatment further reduced blood pressure and partially reversed renal tissues injury. Furthermore, dietary salt reduction with the combination of ARB plus CCB elicited a strong recovery from HS-induced renal tissue injury including the attenuation of inflammation and oxidative stress. These data support the hypothesis that dietary salt reduction with combination therapy of an ARB plus CCB restores glomerular and tubulointerstitial injury in DSS rats.