Matrix Metalloproteinase-2 Knockout and Heterozygote Mice Are Protected from Hydronephrosis and Kidney Fibrosis after Unilateral Ureteral Obstruction.

Matrix Metalloproteinase-2 (Mmp2) is a collagenase known to be important in the development of renal fibrosis. In unilateral ureteral obstruction (UUO) the obstructed kidney (OK) develops fibrosis, while the contralateral (CL) does not. In this study we investigated the effect of UUO on gene expression, fibrosis and pelvic remodeling in the kidneys of Mmp2 deficient mice (Mmp2-/-), heterozygous animals (Mmp2+/-) and wild-type mice (Mmp2+/+).

Unilateral renal ischaemia in rats induces a rapid secretion of inflammatory markers to renal lymph and increased capillary permeability.

A better understanding of the inflammatory process associated with renal ischaemia-reperfusion (IR) injury may be clinically important. In this study we examined the role of the kidney in production of inflammatory mediators by analysing renal lymph after 30 min unilateral occlusion of renal artery followed by 120 min reperfusion, as well as the effect of IR on size selectivity for proteins in both glomerular and peritubular capillaries. All measured mediators increased dramatically in renal hilar lymph, plasma and renal cortical tissue samples and returned to control levels after 120 min reperfusion.

Identification of a common molecular pathway in hypertensive renal damage: comparison of rat and human gene expression profiles.

Background: There is a common structural progression in hypertensive renal damage with early arterial damage and fibrosis in the juxtamedullary cortex.

Method: The present investigation identifies a common pathway using three-gene expression profiles from hypertensive rat models: 60-week-old spontaneously hypertensive rat (SHR), salt-loaded stroke-prone SHR (SHRSP), and the non-clipped kidney after 24 weeks of two-kidney, one-clip hypertension (2K1C). Kidney damage was scored using a specialized system.

Nitric oxide in afferent arterioles after uninephrectomy depends on extracellular L-arginine.

Uninephrectomy (UNX) causes hyperperfusion of the contralateral remaining kidney via increased nitric oxide (NO) synthesis. Although the exact mechanism remains largely unknown, we hypothesize that this would be localized to the afferent arteriole and that it depends on cellular uptake of l-arginine. The experiments were performed in rats 2 days (early) or 6 wk (late) after UNX and compared with controls (Sham) to study acute and chronic effects on NO metabolism.

Arterial damage precedes the development of interstitial damage in the nonclipped kidney of two-kidney, one-clip hypertensive rats.

Background: The progression of damage in the renal cortex has not been investigated in the nonclipped kidney of the two-kidney, one-clip model of renal hypertension. In other hypertensive models, damage has been found to progress from the juxtamedullary cortex (JMC) and outward, which has been attributed to early vascular effects.

Method: The present study investigated the relation between perivascular deposition of collagen and structural damage after 16 and 24 weeks of hypertension in the nonclipped kidney in rats.

Collagen-binding proteins in age-dependent changes in renal collagen turnover: microarray analysis of mRNA expression.

Aging is associated with progressive structural and functional deterioration of the kidney. Among the morphological changes associated with renal aging is an accumulation of extracellular matrix (ECM) in the glomeruli and tubuloinsterstitium, which may ultimately lead to the development of renal fibrosis. The mechanisms governing the regulation of ECM metabolism during renal aging are only incompletely defined.

Long-term risk of ESRD in IgAN; validation of Japanese prognostic model in a Norwegian cohort.

Background: Recently, a Japanese model used to predict 10-year risk of end-stage renal disease (ESRD) in IgA nephropathy (IgAN) patients was published. We tested the applicability of the Japanese model in predicting 10- to 20-year risk of ESRD and all-cause mortality in a cohort of Norwegian IgAN patients.

Methods: A cohort of IgAN patients (1988-2004) were identified in the Norwegian Kidney Biopsy Registry (NKBR) and ESRD or death during follow-up through 2008 was identified through record linkage with the Norwegian Renal Registry (ESRD) and the Norwegian Population Registry (deaths).

Afferent arteriolopathy and glomerular collapse but not segmental sclerosis induce tubular atrophy in old spontaneously hypertensive rats.

In chronic renal disease, the temporal and spatial relationship between vascular, glomerular and tubular changes is still unclear. Hypertension, an important cause of chronic renal failure, leads to afferent arteriolopathy, segmental glomerulosclerosis and tubular atrophy in the juxtamedullary cortex. We investigated the pathological changes of hypertensive renal disease in aged spontaneously hypertensive rats using a large number of serial sections, where we traced and analyzed afferent arteriole, glomerulus and proximal tubule of single nephrons.

Pre-transplant course and risk of kidney transplant failure in IgA nephropathy patients.

Background: There is lack of knowledge to what degree clinical/morphological presentation and course of IgA nephropathy (IgAN) prior to end-stage renal disease are risk factors for graft loss after kidney transplantation.

Material And Methods: Patients with IgAN between 1988 and 2006 (registered in the Norwegian Kidney Biopsy Registry) who later received a kidney transplant (registered in the Norwegian Renal Registry) were included. The cohort was followed up regarding death-censored graft loss throughout 2008.

Are adverse pregnancy outcomes risk factors for development of end-stage renal disease in women with diabetes?

Background: It is unknown whether adverse pregnancy-related outcomes in women with pregestational diabetes are associated with later development of end-stage renal disease (ESRD) or death.

Methods: We linked data from the Medical Birth Registry of Norway with data from the Norwegian Renal Registry and the Norwegian Cause of Death Registry. Data from up to three pregnancies for women with a first singleton delivery from 1967 to 1994 were included and analysed in a cohort design using Cox regression.

Previous preeclampsia and risk for progression of biopsy-verified kidney disease to end-stage renal disease.

Background: A recent study has shown that preeclampsia is an important risk marker for end-stage renal disease (ESRD), but the underlying mechanisms are unclear. The present study investigated whether previous preeclampsia was associated with progression of established kidney disease. Material and methods.

Losartan increases NO release in afferent arterioles during regression of L-NAME-induced renal damage.

Inhibition of nitric oxide synthesis (NOS) induces hypertension and heavy proteinuria. Renal structure and function have shown striking improvement after interventions targeting ANG II or endothelin (ET) receptors in rats recovering after long-term NOS inhibition. To search for mechanisms underlying losartan-assisted regression of renal disease in rodents, we measured NO release and contractility to ET in afferent arterioles (AAs) from Sprague-Dawley rats recovering for 2 wk after 4 wk of N(G)-nitro-L-arginine methyl ester treatment.

AT(1) receptor activation regulates the mRNA expression of CAT1, CAT2, arginase-1, and DDAH2 in preglomerular vessels from angiotensin II hypertensive rats.

Previously, we found increased expression of l-arginine metabolizing enzymes in both kidneys from two-kidney, one-clip (2K1C) hypertensive rats (Helle F, Hultstrom M, Skogstrand T, Palm F, Iversen BM. Am J Physiol Renal Physiol 296: F78-F86, 2009). In the present study, we investigate whether AT(1) receptor activation can induce the changes observed in 2K1C.

Angiotensin II-induced contraction is attenuated by nitric oxide in afferent arterioles from the nonclipped kidney in 2K1C.

Two-kidney, one-clip (2K1C) is a model of renovascular hypertension where we previously found an exaggerated intracellular calcium (Ca(i)(2+)) response to ANG II in isolated afferent arterioles (AAs) from the clipped kidney (Helle F, Vagnes OB, Iversen BM. Am J Physiol Renal Physiol 291: F140-F147, 2006). To test whether nitric oxide (NO) ameliorates the exaggerated ANG II response in 2K1C, we studied ANG II (10(-7) mol/l)-induced calcium signaling and contractility with or without the NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME).

Tetradecylthioacetic acid downregulates cyclooxygenase 2 in the renal cortex of two-kidney, one-clip hypertensive rats.

The effect of tetradecylthioacetic acid (TTA) on the cyclooxygenase (COX) system was investigated in two-kidney, one-clip (2K1C) hypertensive rats. The systolic blood pressure (BP) was increased 6 wk after clipping to 183 +/- 4 vs.127 +/- 3 mmHg in TTA-treated 2K1C rats.

Preeclampsia and the risk of end-stage renal disease.

Background: It is unknown whether preeclampsia is a risk marker for subsequent end-stage renal disease (ESRD).

Methods: We linked data from the Medical Birth Registry of Norway, which contains data on all births in Norway since 1967, with data from the Norwegian Renal Registry, which contains data on all patients receiving a diagnosis of end-stage renal disease (ESRD) since 1980, to assess the association between preeclampsia in one or more pregnancies and the subsequent development of ESRD. The study population consisted of women who had had a first singleton birth between 1967 and 1991; we included data from up to three pregnancies.

Glomerular charge barrier and development of proteinuria in passive Heymann nephritis.

Background/aim: Passive Heymann nephritis (PHN) in rats is a commonly used model of membranous glomerulonephritis in man where the cause of proteinuria is not fully resolved. This study was designed to investigate the role of the glomerular charge barrier in development of PHN proteinuria.

Methods: We studied female Sprague-Dawley rats (n = 33) at days 0, 2, 5 and 14 after induction of PHN by injection of antiserum against renal tubular epithelial antigens (anti-Fx1A).

Low birth weight increases risk for end-stage renal disease.

Case-control studies have shown an association between low birth weight and risk for renal failure. The Medical Birth Registry of Norway, which comprises data on all births in Norway since 1967, and the Norwegian Renal Registry, which comprises data on all patients who have developed ESRD in Norway since 1980, were used to examine whether birth-related variables were associated with risk for ESRD. Of the 2,183,317 children born between 1967 and 2004, 526 were found in the ESRD registry.

Tetradecylthioacetic acid prevents the inflammatory response in two-kidney, one-clip hypertension.

ANG II promotes inflammation through nuclear factor-kappaB (NF-kappaB)-mediated induction of cytokines and reactive oxygen species (ROS). The aim of the present study was to examine the effect of tetradecylthioacetic acid (TTA), a modified fatty acid, on NF-kappaB, proinflammatory markers, ROS, and nitric oxide (NO) production in two-kidney, one-clip (2K1C) hypertension. The 2K1C TTA-treated group had lower blood pressure (128 +/- 3 mmHg) compared with 2K1C nontreated (178 +/- 5 mmHg, P < 0.

Upregulation of tissue inhibitor of metalloproteases-1 (TIMP-1) and procollagen-N-peptidase in hypertension-induced renal damage.

Background: Hypertensive renal damage starts in the juxtamedullary cortex (JMC) and gradually extends towards the outer cortex (OC). The intention of the study was to examine if the increase of fibrous tissue in the JMC of the spontaneously hypertensive rat (SHR) is dependent on an increase of collagen synthesis or a decreased collagen breakdown compared to the normotensive control (WKY).

Methods And Results: The renal damage was evaluated by light microscopy, and the amount of fibrosis was quantified using Sirius red staining.

Long-term risk of cancer in membranous nephropathy patients.

Background: There is a well-known association between membranous nephropathy (MN) and cancer, and patients with MN usually are examined for cancer at the time of diagnosis. The long-term risk of cancer after MN is not well studied.

Study Design: Cohort study with record linkage between the Norwegian Kidney Biopsy Registry and Norwegian Cancer Registry.

Three-dimensional ultrasonography can detect the modulation of kidney volume in two-kidney, one-clip hypertensive rats.

As volume changes are a typical finding in the two-kidney, one-clip hypertensive rat model (2K1C), it is of interest to investigate within what time frame these volume changes occur and their relation to hypertension. Kidney volume changes in Wistar rats were measured by three-dimensional (3D) ultrasonography (USG). Clipped induced stenosis was applied to the left renal artery in 11-wk-old animals (n = 8), using age-matched nonclipped rats as controls (n = 7).

Differential effect of tetradecythioacetic acid on the renin-angiotensin system and blood pressure in SHR and 2-kidney, 1-clip hypertension.

The tetradecythioacetic acid (TTA) is a modified fatty acid known to exhibit pleiotropic effects. First, we compared the effect of TTA on the blood pressure in spontaneously hypertensive rats (SHR) with two-kidney, one-clip (2K1C)-hypertensive rats. Second, we examined mechanisms involved in the blood pressure reduction.

Short-term ANG II produces renal vasoconstriction independent of TP receptor activation and TxA2/isoprostane production.

The relative contributions of vasoconstrictor and of dilator systems are balanced in health. The balance is reset in disease, often favoring a predominant role of vasoconstrictors, perhaps due to positive interactions between constrictor systems. For example, in hypertension, chronic high levels of angiotensin II (ANG II) stimulate the production of thromboxane (TxA2/PGH2) and/or isoprostane that activate constrictor thromboxane prostanoid (TP) receptors in the vasculature.

Prevention of hypertension and organ damage in 2-kidney, 1-clip rats by tetradecylthioacetic acid.

Dietary lipids are reported to affect the blood pressure in both humans and experimental animal models with hypertension. In the present study, 2-kidney, 1-clip (2K1C) hypertensive rats were treated with the modified fatty acid tetradecylthioacetic acid (TTA) from the time of clipping or after hypertension was established. TTA treatment attenuated the development of hypertension and reduced established 2K1C hypertension.