Blood pressure and indices of glomerular filtration area in hypertensive and normotensive Prague rats

The involvement of the kidney in the pathogenesis of hypertension has long been recognised, although the specific renal mechanisms underlying this phenomenon are still unknown. A current hypothesis attributes hyper tension to a reduction in glomerular filtration area by glomerular loss, The present study analyses the relationship between glomerular number and volume and conscious systolic blood pressure (SBP) in 4- to 53-week-old hypertensive (PHR) and normotensive (PNR) rats of the Prague strain. Adult PHRs had higher SEP, were larger and had larger kidneys than PNRs, but 20% fewer glomeruli, A significant negative correlation between SEP and glomerular number was found in PHR males, but not in PHR females or PNRs. There was no correlation at all between glomerular volume and SEP and, in young animals, both SEP and glomerular number were higher in PHRs than in PNRs. In addition, in adult PHRs, glomerular volume and SEP were higher in males than in females. In summary, a generally valid, causal relation-ship linking raised blood pressure to decreased glomerular number or volume could not be demonstrated in the Prague rat model of genetically determined hypertension. The nature of the renal mechanism(s) determining the hypertension in this model remains unknown. Copyright (C) 2000 S. Karger AG, Basel

Hyperglycemia and Hyperlipidemia Act Synergistically to Induce Renal Disease in LDL Receptor-Deficient BALB Mice

Diabetic nephropathy is the leading cause of end-stage renal disease in Western countries, but only a portion of diabetic patients develop diabetic nephropathy. Dyslipidemia represents an important aspect of the metabolic imbalance in diabetic patients. In this study, we addressed the impact of combined hyperlipidemia and hyperglycemia on renal pathology. Kidneys from wildtype (WT) or LDL receptor-deficient BALB/cBy mice (BALB. LDLR -/-) were examined at 22 weeks of age. Diabetes was induced by administration of streptozotocin and mice were randomly assigned to either standard chow or Western diet. Chow fed BALB. LDLR -/- mice did not demonstrate renal abnormalities, whereas BALB. LDLR -/- mice fed a Western diet showed occasional glomerular and tubulointerstitial foam cells. Diabetic WT mice had modestly increased glomerular cellularity and extracellular matrix. Hyperlipidemic and diabetic BALB. LDLR -/- mice exhibited an increase in glomerular cellularity and extracellular matrix, accumulation of glomerular and tubulointerstitial foam cells and mesangial lipid deposits. The tubular epithelium demonstrated pronounced lipid induced tubular degeneration with increased tubular epithelial cell turnover. Hyperlipidemia and hyperglycemia seem to act synergistically in inducing renal injury in the BALB. LDLR-/- mouse. This model of diabetic nephropathy is unique in its development of tubular lesions and may represent a good model for hyperlipidemia-exacerbated diabetic nephropathy. Copyright (C) 2004 S. Karger AG, Basel

Altered density of glomerular binding sites for atrial natriuretic factor in bile duct-ligated rats with ascites

The renal response to atrial natriuretic factor is blunted in cirrhosis with ascites. This might be due to alterations of renal receptors for atrial natriuretic factor. Therefore density and affinity of glomerular atrial natriuretic factor binding sites of bile duct-ligated rats with ascites (n = 10) and of sham-operated controls (n = 10) were determined. Glomerular atrial natriuretic factor binding sites were identified to be of the B-(biologically active) and C-(clearance) receptor type. Discrimination and quantitative determination of B and C receptors for atrial natriuretic factor were achieved by displacement experiments with atrial natriuretic factor(99-126) or des(18-22)atrial natriuretic factor(4-23), an analogue binding to C receptors only. Density of total glomerular atrial natriuretic factor binding sites was significantly increased in bile duct-ligated rats (3,518 ± 864 vs. 1,648 ± 358 fmol/mg protein; p < 0.05). This was due to a significant increase of C-receptor density (3,460 ± 866 vs. 1,486 ± 363 fmol/mg protein; p < 0.05), whereas density of B receptors was not significantly different in bile duct-ligated rats (58 ± 11 vs. 162 ± 63 fmol/mg protein). Affinity of atrial natriuretic factor to its glomerular binding sites did not differ significantly between both groups. These data suggest that an altered glomerular atrial natriuretic factor receptor density could be involved in the renal resistance to atrial natriuretic factor in cirrhosis with ascites

CXCL16 and oxLDL are induced in the onset of diabetic nephropathy

Diabetic nephropathy (DN) is a major cause of end-stage renal failure worldwide. Oxidative stress has been reported to be a major culprit of the disease and increased oxidized low density lipoprotein (oxLDL) immune complexes were found in patients with DN. In this study we present evidence, that CXCL16 is the main receptor in human podocytes mediating the uptake of oxLDL. In contrast, in primary tubular cells CD36 was mainly involved in the uptake of oxLDL. We further demonstrate that oxLDL down-regulated α3-integrin expression and increased the production of fibronectin in human podocytes. In addition, oxLDL uptake induced the production of reactive oxygen species (ROS) in human podocytes. Inhibition of oxLDL uptake by CXCL16 blocking antibodies abrogated the fibronectin and ROS production and restored α3 integrin expression in human podocytes. Furthermore we present evidence that hyperglycaemic conditions increased CXCL16 and reduced ADAM10 expression in podocytes. Importantly, in streptozotocin-induced diabetic mice an early induction of CXCL16 was accompanied by higher levels of oxLDL. Finally immunofluorescence analysis in biopsies of patients with DN revealed increased glomerular CXCL16 expression, which was paralleled by high levels of oxLDL. In summary, regulation of CXCL16, ADAM10 and oxLDL expression may be an early event in the onset of DN and therefore all three proteins may represent potential new targets for diagnosis and therapeutic intervention in DN

Permselectivity of the glomerular wall examined with iron compound tracer

Rat kidney endothelial cell morphology was examined after introducing iron colloid particles of positive or negative charge to investigate the relationship between the electric charge and permeation through the glomerular capillary. The kidneys were first perfused with Hanks' solution through the renal arteries and then with iron colloid particles of positive or negative charge. The iron colloid particles of positive charge were prepared with ferric chloride and cacodylate solutions, and the negative particles were prepared with iron chondroitin sulfate colloid particles. The iron colloid particles of positive charge adhered to the surface of endothelial cells of the glomerular capillaries, as well as the arterioles, capillaries and venules. Some particles were taken up by pinocytosis, accumulated in the glomerular basement membrane and appeared in the urinary spaces passing through the filtration slits of podocytes. Iron colloid particles of negative charge neither adhered to the endothelial cells nor were taken by the cells. They did not permeate into the urinary spaces. Permeation into the tubular lumen through the peritubular venules was not observed with particles of positive or negative charge.</p

Postnatal maturation of the glomerular filtration rate in conventional growing piglets as potential juvenile animal model for preclinical pharmaceutical research

Adequate animal models are required to study the preclinical pharmacokinetics (PK), pharmacodynamics (PD) and safety of drugs in the pediatric subpopulation. Over the years, pigs were presented as a potential animal model, since they display a high degree of anatomical and physiological similarities with humans. To assess the suitability of piglets as a preclinical animal model for children, the ontogeny and maturation processes of several organ systems have to be unraveled and compared between both species. The kidneys play a pivotal role in the PK and PD of various drugs, therefore, the glomerular filtration rate (GFR) measured as clearance of endogenous creatinine (Jaffe and enzymatic assay) and exo-iohexol was determined in conventional piglets aging 8 days (n = 16), 4 weeks (n = 8) and 7 weeks (n = 16). The GFR data were normalized to bodyweight (BW), body surface area (BSA) and kidney weight (KW). Normalization to BSA and KW showed an increase in GFR from 46.57 to 100.92 mL/min/m2 and 0.49 to 1.51 mL/min/g KW from 8 days to 7 weeks of age, respectively. Normalization to BW showed a less pronounced increase from 3.55 to 4.31 mL/min/kg. The postnatal development of the GFR was comparable with humans, rendering the piglet a convenient juvenile animal model for studying the PK, PD and safety of drugs in the pediatric subpopulation. Moreover, to facilitate the assessment of the GFR in growing piglets in subsequent studies, a formula was elaborated to estimate the GFR based on plasma creatinine and BW, namely eGFR =1.879 × BW^1.092/Pcr^0.600

Biological Pathways and Potential Targets for Prevention and Therapy of Chronic Allograft Nephropathy

Renal transplantation (RT) is the best option for patients with end-stage renal disease, but the half-life is limited to a decade due to progressive deterioration of renal function and transplant failure from chronic allograft nephropathy (CAN), which is the leading cause of transplant loss. Extensive research has been done to understand the pathogenesis, the biological pathways of fibrogenesis, and potential therapeutic targets for the prevention and treatment of CAN. Despite the advancements in the immunosuppressive agents and patient care, CAN continues to remain an unresolved problem in renal transplantation. The aim of this paper is to undertake a comprehensive review of the literature on the pathogenesis, biological pathways of RT fibrogenesis, and potential therapeutic targets for the prevention and therapy of CAN

Protease-activated receptor 1 mediates thrombin-dependent, cell-mediated renal inflammation in crescentic glomerulonephritis.

Protease-activated receptor (PAR)-1 is a cellular receptor for thrombin that is activated after proteolytic cleavage. The contribution of PAR-1 to inflammatory cell-mediated renal injury was assessed in murine crescentic glomerulonephritis (GN). A pivotal role for thrombin in this model was demonstrated by the capacity of hirudin, a selective thrombin antagonist, to attenuate renal injury. Compared with control treatment, hirudin significantly reduced glomerular crescent formation, T cell and macrophage infiltration, fibrin deposition, and elevated serum creatinine, which are prominent features of GN. PAR-1-deficient (PAR-1(-/-)) mice, which have normal coagulation, also showed significant protection from crescentic GN compared with wild-type mice. The reductions in crescent formation, inflammatory cell infiltration, and serum creatinine were similar in PAR-1(-/-) and hirudin-treated mice, but hirudin afforded significantly greater protection from fibrin deposition. Treatment of wild-type mice with a selective PAR-1-activating peptide (TRAP) augmented histological and functional indices of GN, but TRAP treatment did not alter the severity of GN in PAR(-/-) mice. These results indicate that activation of PAR-1 by thrombin or TRAP amplifies crescentic GN. Thus, in addition to its procoagulant role, thrombin has proinflammatory, PAR-1-dependent effects that augment inflammatory renal injury

Identification of novel molecular signatures of IgA nephropathy through an integrative -omics analysis

IgA nephropathy (IgAN) is the most prevalent among primary glomerular diseases worldwide. Although our understanding of IgAN has advanced significantly, its underlying biology and potential drug targets are still unexplored. We investigated a combinatorial approach for the analysis of IgAN-relevant -omics data, aiming at identification of novel molecular signatures of the disease. Nine published urinary proteomics datasets were collected and the reported differentially expressed proteins in IgAN vs. healthy controls were integrated into known biological pathways. Proteins participating in these pathways were subjected to multi-step assessment, including investigation of IgAN transcriptomics datasets (Nephroseq database), their reported protein-protein interactions (STRING database), kidney tissue expression (Human Protein Atlas) and literature mining. Through this process, from an initial dataset of 232 proteins significantly associated with IgAN, 20 pathways were predicted, yielding 657 proteins for further analysis. Step-wise evaluation highlighted 20 proteins of possibly high relevance to IgAN and/or kidney disease. Experimental validation of 3 predicted relevant proteins, adenylyl cyclase-associated protein 1 (CAP1), SHC-transforming protein 1 (SHC1) and prolylcarboxypeptidase (PRCP) was performed by immunostaining of human kidney sections. Collectively, this study presents an integrative procedure for -omics data exploitation, giving rise to biologically relevant results