Kidney Remodeling Research Articles

Kidney remodeling in pregnant women with somatic disease

Kidney remodeling in pregnant women with somatic disease

The danger control concept in kidney disease: mesangial cells

Kidney remodeling is a response to intrinsic or extrinsic triggers of kidney injury. Injury initiates a set of universal response programs that were positively selected through evolution to control potentially life-threatening dangers and to regain homeostasis, including tissue repair. These danger control programs are (i) clotting, to control the risk of bleeding; (ii) inflammation, to control the risk of infection; (iii) epithelial repair; (iv) mesenchymal repair; and (v) scar resolution or minimization. In this review we focus on the role of mesangial cells in glomerular disorders and how their behaviors follow these danger control programs. We review the role of mesangial cells in glomerular coagulation and fibrinolysis, as well as their role in triggering glomerular inflammation and mesangioproliferative disorders. Furthermore, we discuss how the mesangium self-repairs, how podocyte injury triggers a "mesenchymal healing"-kind of response that leads to glomerular fibrosis and sclerosis. Thus, we can better appreciate the contribution of mesangial cells to glomerular pathology when we understand their behavior as an attempt to support the evolutionally conserved universal danger control programs. However, these mechanisms often result in maladaptive processes that destroy the complex glomerular ultrastructure rather than help to regain tissue homeostasis.

Four danger response programs determine glomerular and tubulointerstitial kidney pathology

Renal biopsies commonly display tissue remodeling with a combination of many different findings. In contrast to trauma, kidney remodeling largely results from intrinsic responses, but why? Distinct danger response programs were positively selected throughout evolution to survive traumatic injuries and to regenerate tissue defects. These are: (1) clotting to avoid major bleeding, (2) immunity to control infection, (3) epithelial repair and (4) mesenchymal repair. Collateral damages are acceptable for the sake of host survival but causes for kidney injury commonly affect the kidneys in a diffuse manner. This way, coagulation, inflammation, deregulated epithelial healing or fibrosis contribute to kidney remodeling. Here, I focus on how these ancient danger response programs determine renal pathology mainly because they develop in a deregulated manner, either as insufficient or overshooting processes that modulate each other. From a therapeutic point of view, immunopathology can be prevented by suppressing sterile renal inflammation, a useless atavism with devastating consequences. In addition, it appears as an important goal for the future to promote podocyte and tubular epithelial cell repair, potentially by stimulating the differentiation of their newly discovered intrarenal progenitor cells. By contrast, it is still unclear whether selectively targeting renal fibrogenesis can preserve or bring back lost renal parenchyma, which would be required to maintain or improve kidney function. Thus, renal pathology results from ancient danger responses that evolved because of their evolutional benefits upon trauma. Understanding these causalities may help to shape the search for novel treatments for kidney disease patients.

Urinary Proteome Analysis at 5-Year Followup of Patients With Nonoperated Ureteropelvic Junction Obstruction Suggests Ongoing Kidney Remodeling

Severe ureteropelvic junction obstruction is treated surgically. However, for milder cases most clinical teams adopt a watchful waiting approach and only operate in the presence of significant decline of renal function combined with severe hydronephrosis. Little is known about the long-term consequences of ureteropelvic junction obstruction. Using capillary electrophoresis coupled with mass spectrometry, we analyzed the urinary proteome of 42 patients with ureteropelvic junction obstruction 5 years postoperatively or 5 years following spontaneous resolution. At 5-year followup urinary proteomes were similar between patients with early surgical correction of ureteropelvic junction obstruction and age matched controls. In contrast, urinary proteomes differed significantly between conservatively followed patients and controls. Analyses of the proteomic differences suggested ongoing renal or ureteral remodeling in the conservatively followed patients that was not visible clinically. Long-term followup studies are warranted in patients with ureteropelvic junction obstruction, especially those followed conservatively, to determine whether the observed changes in the urinary proteomes become clinically relevant at a later stage.

High glucose activates HIF-1-mediated signal transduction in glomerular mesangial cells through a carbohydrate response element binding protein

High glucose evokes a variety of signals in mesangial cells that alter cellular functions responsible for the development of diabetic glomerulopathy. The hypoxia-inducible factor-1alpha (HIF-1alpha) regulates cellular homeostasis under hypoxic conditions, but it also has pleiotropic effects in response to cellular stresses at normoxia. Here we determined whether HIF-1alpha has a role in the regulation of mesangial cells in hyperglycemia. In the streptozotocin-induced diabetic mouse model, glomerular mesangial cells had a significant increase in HIF-1alpha expression in the nucleus. In cultured mesangial cells, high glucose enhanced the expression of HIF-1alpha and its target genes known to be involved in the development of diabetic glomerulopathy. A glucose-responsive carbohydrate response element binding protein (ChREBP) was found to have a critical role in the transcriptional upregulation of HIF-1alpha and downstream gene expression in mesangial cells exposed to high glucose. Knockdown of HIF-1alpha or ChREBP in mesangial cells abrogated the high glucose-mediated perturbation of gene expression. Our results show that ChREBP and HIF-1alpha mediate gene regulation in mesangial cells. Further studies will be needed to find out whether these findings are relevant to the development of the diabetic nephropathy.

Abstract 5155: Superoxide-Dependent Cathepsin Activation System is Associated with Hypertensive Renal Remodeling and Represents a Target for Statin

Objective: Cathepsins are members of the cysteine protease family that participate in various types of tissue remodeling. Given that NADPH oxidase is implicated in protease activation, we examined the possible role of NADPH oxidase-dependent cathepsin activation in hypertensive renal remodeling with heart failure (HF) in Dahl salt-sensitive (DS) rats. Methods and Results: DS rats maintained on a high-salt diet were randomly assigned to four groups (( n = 10 for each group) that were treated with either vehicle (0.5% carboxymethyl cellulose; CMC), low-dose pitavastatin (1 mg/kg/d; Pitava-L), high-dose pitavastatin (3 mg/kg/d; Pitava-H), E64d (a cysteine protease inhibitor), or pitavastatin from 12 to 19 weeks of age. Rats fed a low-salt diet served as controls. Marked cortical mesangial matrix expansion and the levels of collagen type I and III, angiotensin II type receptor 1 (AT 1 R), and mineralocorticoid receptor (MR) mRNAs and the activity of cathepsin S and its protein in the kidney were increased in the CMC group with HF at 19 weeks compared with control rats. Immunostaining showed strong signaling for cathepsin S in the glomerular cells in the kidney of HF rats. Treatment with either dose of pitavastatin reduced the extent of fibrosis, the collagen type I and III mRNAs, and cathepsin S activity and its protein expression compared with those in CMC rats. The decrease in the ratio of reduced to oxidized glutathione and the increase in macrophage infiltration and NADPH oxidase activity as well as its subunits (including p22phox and gp91phox) and superoxide production apparent in the kidney of CMC rats were also inhibited by pitavastatin in a dose-dependent manner. These benefic effects of pitavastatin were partially mimicked by E64d and accompanied by amelioration of kidney fibrosis. Furthermore, both doses of pitavastatin reduced the levels of AT1R and MR mRNAs but not plasma angiotensin II levels. Conclusions: This is the first report showing that cathepsins are likely to trigger and promote kidney remodeling, and that pitavastatin suppresses the cathepsin activation system by the inhibiting NADPH oxidase-dependent superoxide anion production, leading to the prevention of kidney remodeling in hypertensive HF rats.

Kidney tubular epithelium is restored without replacement with bone marrow–derived cells during repair after ischemic injury

The kidney has the ability to restore the structural and functional integrity of the proximal tubule, which undergoes extensive epithelial cell death after prolonged exposure to ischemia. In order to study the role that adult bone marrow-derived stem cells might play in kidney remodeling after injury, we employed a murine model of ischemia/reperfusion (I/R) injury in which the degree of injury, dysfunction, repair, tubular cell proliferation and functional recovery have been characterized [Park KM, et al, J Biol Chem 276:11870-11876, 2001]. We generated chimeric mice using marrow from mice expressing the bacterial LacZ gene, or the enhanced green fluorescence protein (eGFP) gene, or from male mice transplanted into female mice. The establishment of chimerism was confirmed at 6 weeks following transplantation in each case. I/R injury was induced in chimeric mice by occluding the renal arteries and veins with microaneurysm clamps for 30 minutes. After functional recovery in the eGFP chimeras, although there were many interstitial cells, no tubular cells were derived from bone marrow cells. In the bacterial beta-galactosidase (beta-gal) chimeric mice we found evidence of mammalian (endogenous) beta-gal by 5-bomo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-gal) staining, but not bacterial beta-gal in tubule cells. Detection of the Y chromosome by fluorescence in situ hybridization (FISH) in the postischemic kidneys of gender-mismatched chimeras revealed Y chromosome positivity only in the nuclei of interstitial cells, when scrutinized by deconvolution microscopy. In our model of I/R injury there was a large amount of proliferation of surviving, injured tubular cells indicating that the injured tubule is repopulated by daughter cells of surviving tubular cells. Analysis of the phenotype of interstitial and vascular cells following I/R injury revealed small numbers of peritubular endothelial cells to be derived from bone marrow cells that may serve in the repair process.

Apolipoprotein E and progression of chronic kidney disease.

Apolipoprotein E (APOE) genetic variation has been implicated in diabetic nephropathy with the epsilon2 allele increasing and the epsilon4 allele decreasing risk. APOE allelic associations with chronic kidney disease beyond diabetic nephropathy are unknown, with no studies reported in high-risk African American populations. To quantify the risk of chronic kidney disease progression associated with APOE in a population-based study including white, African American, diabetic, and nondiabetic individuals. Prospective follow-up (through January 1, 2003) of Atherosclerosis Risk in Communities (ARIC) study participants, including 3859 African American and 10,661 white adults aged 45 to 64 years without severe renal dysfunction at baseline in 1987-1989, sampled from 4 US communities. Incident chronic kidney disease progression, defined as hospitalization or death with kidney disease or increase in serum creatinine level of 0.4 mg/dL (35 micromol/L) or more above baseline, examined by APOE genotypes and alleles. During median follow-up of 14 years, chronic kidney disease progression developed in 1060 individuals (incidence per 1000 person-years: 5.5 overall; 8.8 in African Americans and 4.4 in whites). Adjusting for major chronic kidney disease risk factors, epsilon2 moderately increased and epsilon4 decreased risk of disease progression (likelihood ratio test, P = .03). Further adjustment for low- and high-density lipoprotein cholesterol and triglycerides did not attenuate relative risks (RRs) (epsilon2: 1.08 [95% CI, 0.93-1.25] and epsilon4: 0.85 [95% CI, 0.75-0.95] compared with epsilon3; likelihood ratio test, P = .008). Epsilon4 decreased risk of end-stage renal disease (RR, 0.60 [95% CI, 0.43-0.84]). Epsilon2 was associated with a decline in renal function (RR, 1.25 [95% CI, 1.02-1.53]), though not with events, such as hospitalizations or end-stage renal disease. Risks were similar stratified by race, sex, diabetes, and hypertension (all P values for interaction >.05). Excess risk of chronic kidney disease in African Americans was not explained by APOE alleles. APOE variation predicts chronic kidney disease progression, independent of diabetes, race, lipid, and nonlipid risk factors. Our study suggests that nonlipid-mediated pathways, such as cellular mechanisms of kidney remodeling, may be involved in the association of APOE alleles and progression of chronic kidney disease.

Kallikrein gene transfer reduces renal fibrosis, hypertrophy, and proliferation in DOCA-salt hypertensive rats

In DOCA-salt hypertension, renal kallikrein levels are increased and may play a protective role in renal injury. We investigated the effect of enhanced kallikrein levels on kidney remodeling of DOCA-salt hypertensive rats by systemic delivery of adenovirus containing human tissue kallikrein gene. Recombinant human kallikrein was detected in the urine and serum of rats after gene delivery. Kallikrein gene transfer significantly decreased DOCA- and salt-induced proteinuria, glomerular sclerosis, tubular dilatation, and luminal protein casts. Sirius red staining showed that kallikrein gene transfer reduced renal fibrosis, which was confirmed by decreased collagen I and fibronectin levels. Furthermore, kallikrein gene delivery diminished myofibroblast accumulation in the interstitium of the cortex and medulla, as well as transforming growth factor (TGF)-beta1 immunostaining in glomeruli. Western blot analysis and ELISA verified the decrease in immunoreactive TGF-beta1 levels. Kallikrein gene transfer also significantly reduced kidney weight, glomerular size, proliferating tubular epithelial cells, and macrophages/monocytes. Reduction of proliferation and hypertrophy was associated with reduced levels of the cyclin-dependent kinase inhibitor p27(Kip1), and the phosphorylation of c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). The protective effects of kallikrein were accompanied by increased urinary nitrate/nitrite and cGMP levels, and suppression of superoxide formation. These results indicate that kallikrein protects against mineralocorticoid-induced renal fibrosis glomerular hypertrophy, and renal cell proliferation via inhibition of oxidative stress, JNK/ERK activation, and p27(Kip1) and TGF-beta1 expression.

Maternal gestational protein-calorie restriction decreases the number of glomeruli and causes glomerular hypertrophy in adult hypertensive rats

This work analyzed the renal function and structure in offspring rats that were submitted to maternal protein-calorie restriction during prenatal or lactation periods. Kidneys from adult offspring were studied. Animals from mothers that were submitted to food restriction were separated in 3 groups: control, prenatal restriction, and lactation restriction. Blood pressure, microalbuminuria, and glomerular filtration rate were determined. Kidney cortical remodeling was analyzed with stereology; volume-weighted glomerular volume and the number of glomeruli were estimated. Adult prenatal restriction offspring showed enhanced microalbuminuria, decreased glomerular filtration rate, and hypertension; their kidneys showed a smaller number of hypertrophied glomeruli than control and lactation restriction animals. Maternal prenatal protein-calorie restriction in rats causes kidney disease in adult offspring, which is characterized by hypertension and renal dysfunction and suggests secondary kidney remodeling because of an impairment of glomerulogenesis.

Plasticity of kidney cells: Role in kidney remodeling and scarring

The progression of renal scarring and the associated loss of function remains one of the main challenges in nephrology. Until recently, the glomerular and tubulointerstitial scarring processes were thought to involve primarily interactions between infiltrating inflammatory cells and resident renal cells culminating in loss of renal cells and their replacement by extracellular collagenous matrix (ECM). This review focuses on new aspects of renal response to injury and remodeling. Emphasis is on the plasticity of renal cells with the capacity of both glomerular and tubular cells to assume a range of phenotypes during the remodeling process. Both glomerular and tubular epithelial cells regress to primitive/embryonic mesenchymal phenotype in response to injury. This reverse embryogenesis is a key step in renal healing and scarring. In addition to the plasticity of intrinsic renal cells, it is becoming apparent that renal remodeling in health and disease involves the migration of progenitor hematopoietic stem cells into the kidneys. These cells assume various glomerular and tubular epithelial phenotype. They are also involved in the evolution of lesions toward healing or scarring. A better understanding of some of these key events in renal remodeling and their mediators may open the way to new interventions based on their manipulations and aimed at favoring renal healing and preventing scarring.

Effects of AT1 receptor antagonist on proteoglycan gene expression in hypertensive rats.

Proteoglycans are an important component of the extracellular matrix, and are thought to play multiple roles not only in kidney remodeling, but also in regulating glomerular permeability, and in modulating the activity of other cytokines and growth factors. The aim of this study was to examine the gene expressions of proteoglycan core proteins in hypertensive rat kidneys, and their modulation by AT1 receptor antagonist. SHRSP/Izm rats and normotensive control WKY/Izm rats on a normal salt diet were treated with or without the AT1 receptor antagonist candesartan cilexetil (1 mg/kg/day) from 10 weeks to 22 weeks. At the end of the treatment period, renal tissue was excised, and gene expressions of the proteoglycan core proteins versican, perlecan, decorin, and biglycan were examined by Northern blot analysis and RT-PCR. Treatment with candesartan cilexetil caused significant decreases in blood pressure and amelioration of proteinuria and renal histological scores in the SHRSP/Izm rats. Compared to WKY/Izm rats, expression of biglycan mRNA showed a small increase in SHRSP/Izm rats which did not attain statistical significance. On the other hand, treatment with candesartan caused significant reductions in biglycan and decorin mRNA in the SHRSP/Izm rats. In contrast, the level of versican mRNA appeared to be increased after candesartan treatment. These results suggest that treatment with AT1 receptor antagonist was associated with diverse changes in renal proteoglycan gene expression in SHRSP/Izm rats. These changes could contribute to the beneficial effects of AT1 receptor antagonist on tissue remodeling and inhibition of disease progression in hypertensive rat kidneys.

Calcium ions as extracellular, first messengers.

Ca2+ concentration in the extracellular fluids ([Ca2+]o) is essential for a number of vital processes from bone formation to blood clotting. For this reason, it is necessary that [Ca2+]o must be strictly controlled. Mammalian species have developed a complex homeostatic system that includes parathyroid glands, kidney and bone. The extracellular Ca(2+)-sensing receptor (CaR) is an essential component of this system, regulating parathyroid hormone secretion, calcium excretion by the kidney and bone remodeling. Initially identified from bovine parathyroid glands (1), within the five years following its identification CaR presence has rapidly been extended to organs where the link with mineral ion metabolism has not been elucidated (i.e., brain, stomach, eye, skin, and many other epithelial cells) (see 2 for review). This review will address the discovery of a novel class of ionsensing receptors, receptor-effector coupling, and the roles of the CaR inside and outside the Ca2+o homeostatic system.