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Journal: American journal of physiology. Renal physiology

28

Tubulointerstitial macrophage infiltration is a hallmark of chronic kidney disease (CKD) involved in the progression of renal fibrosis. Pirfenidone is a newly identified anti-fibrotic drug, the potential mechanism of which remains unclear. The aim of this study was to investigate the effects of pirfenidone on M1/M2 macrophage infiltration in nephrectomized rats. Nephrectomized rats were treated with pirfenidone by gavage for 12 weeks. 24-h urinary protein, NAG activity, systolic blood pressure (SBP) and CRP were determined. Paraffin-embedded sections were stained for CD68 (-), CCR7 (-) and CD163 (-) macrophages. MCP-1 and MIP-1α, as well as M1 and M2 macrophages secretory markers were evaluated by real-time RT-PCR and western blotting analysis. Pirfenidone significantly improved the elevated proteinuria and NAG activity from week 2 onward after surgery. Pirfenidone attenuated interstitial fibrosis and decreased expression of fibrotic markers including TGF-β1, CTGF, α-SMA, fibronectin and FSP-1. Pirfenidone significantly decreased the infiltrating macrophages. The number of M1 and M2 macrophages was significantly lower after pirfenidone treatment. MCP-1 and MIP-1α were increased in nephrectomized rats at mRNA and protein levels. Pirfenidone treatment significantly inhibited their expression. The TNF-α, IL-6 and iNOS expressed by M1 macrophages were increased in nephrectomized rats, and pirfenidone significantly attenuated their expression. Pirfenidone treatment also significantly decreased arginase-1, dectin-1, CD206 and CD86 expressed by M2 macrophages. Thus, Pirfenidone inhibits M1 and M2 macrophage infiltration in 5/6 nephrectomized rats, which suggests its efficacy in the early and late periods of renal fibrosis.

Concepts: Chronic kidney disease, Kidney, Molecular biology, Atherosclerosis, Fibrosis, Macrophage, Blood pressure, Western blot

27

Nephron number (Nglom) and size (Vglom) are correlated with risk for chronic cardiovascular and kidney disease and may be predictive of renal allograft viability. Unfortunately, there are no techniques to assess Nglom and Vglom in intact kidneys. This work demonstrates the use of cationized ferritin (CF) as a magnetic resonance imaging (MRI) contrast agent to measure Nglom and Vglom in functioning human kidneys donated to science. The kidneys were obtained from patients with varying levels of cardiovascular and renal disease. CF was intravenously injected into three functioning human kidneys. A fourth naive control kidney was perfused with saline. After fixation, immunofluorescence and electron microscopy confirmed binding of CF to the glomerulus. The intact kidneys were imaged with 3D MRI and CF-labeled glomeruli appeared as punctate spots. Custom software identified, counted, and measured the apparent volumes of CF-labeled glomeruli, with an ~6% false positive rate. These measurements were comparable to stereological estimates. The MRI-based technique yielded a novel whole-kidney distribution of glomerular volumes. Histopathology demonstrated that the distribution of CF-labeled glomeruli may be predictive of glomerular and vascular disease. Variations in CF distribution were quantified using spectral analyses and may be a useful marker of glomerular sclerosis. This is the first report of direct measurement of glomerular number and volume in intact human kidneys.

Concepts: Kidney, Glomerulus, Nephron, Measurement, Medical imaging, Magnetic resonance imaging, Contrast medium, Renal corpuscle

27

Unilateral ureteral obstruction (UUO), a widely used model of chronic kidney disease and congenital obstructive uropathy, causes proximal tubular injury and formation of atubular glomeruli. Because transforming growth factor-β1 (TGF-β1) is a central regulator of renal injury, neonatal and adult mice were subjected to complete UUO under general anesthesia and treated with vehicle or ALK5 TGF-β1 receptor inhibitor (IN-1130, 30 mg/kg/d). After 14 days, glomerulotubular integrity and proximal tubular mass were determined by morphometry of Lotus tetragonolobus lectin distribution, and the fraction of atubular glomeruli was determined by serial section analysis of randomly selected individual glomeruli. Glomerular area, macrophage infiltration, fibronectin distribution and interstitial collagen were measured by morphometry. Compared to placebo, inhibition of TGF-β1 by IN-1130 decreased apoptosis and formation of atubular glomeruli, prevented parenchymal loss, increased glomerular area and glomerulotubular integrity, and increased proximal tubule fraction of the adult obstructed kidney parenchyma from 17% to 30% (p<0.05, respectively). IN-1130 decreased macrophage infiltration and fibronectin and collagen deposition in the adult obstructed kidney by ~50% (p<0.05, respectively). In contrast to these salutary effects in the adult, IN-1130 caused widespread necrosis in obstructed neonatal kidneys. We conclude that whereas IN-1130 reduces obstructive injury in adult kidneys through preservation of glomerulotubular integrity and proximal tubular mass, TGF-β1 inhibition aggravates obstructive injury in neonates. These results indicate that while caution is necessary in treating congenital uropathies, ALK5 inhibitors may prevent nephron loss due to adult kidney disease.

Concepts: Chronic kidney disease, Kidney, Glomerulus, Bowman's capsule, Nephron, Renal cortex, Distal convoluted tubule, Renal corpuscle

22

Renal fibrosis is defined as the excessive deposition and modification of extracellular matrix (ECM) in the renal parenchyma in response to injury and inflammation, resulting in renal function loss. This condition is common to many chronic kidney diseases (CKD) that occur under diverse pathological conditions, such as diabetic and hypertensive nephropathy. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in regulation of cardiovascular functions and pathogenesis of various cardiovascular diseases. S1P has also been seen as an important regulator of fibrotic diseases, playing significant roles in the differentiation of fibroblasts to myofibroblasts and in the induction of inflammatory responses in early stages of fibrotic diseases. This mini review summarizes recent research findings on the importance of the sphingosine kinase-1 (SphK1)/S1P/S1P receptor (S1PR) axis in interaction with other classic fibrotic signaling pathways and the immune inflammatory response to reveal novel therapeutic targets for treatment of renal fibrosis.

Concepts: Immune system, Inflammation, Renal failure, Chronic kidney disease, Nephrology, Extracellular matrix, Pathology, Sphingosine

6

Maintenance of adequate renal function after living kidney donation is important for donor outcome. Overweight donors, in particular, may have an increased risk for end-stage kidney disease (ESKD), and young female donors have an increased preeclampsia risk. Both of these risks may be associated with low postdonation renal functional reserve (RFR). Because we previously found that higher body mass index (BMI) was associated with lower postdonation RFR, we now studied the relationship between BMI and RFR in young female donors. RFR, the rise in glomerular filtration rate (GFR) (125I-iothalamate clearance) during dopamine, was measured in female donors (<45 yr) before and after kidney donation. Donors who are overweight (BMI >25) and nonoverweight donors were compared by Student’s t-test; the association was subsequently explored with regression analysis. We included 105 female donors [age 41 (36-44) median(IQR)] with a BMI of 25 (22-27) kg/m2. Predonation GFR was 118 (17) ml/min [mean(SD)] rising to 128 (19) ml/min during dopamine; mean RFR was 10 (10) ml/min. Postdonation GFR was 76 (13) ml/min, rising to 80 (12); RFR was 4 (6) ml/min ( P < 0.001 vs. predonation). In overweight donors, RFR was fully lost after donation (1 ml/min vs. 10 ml/min predonation, P < 0.001), and BMI was inversely associated with RFR after donation, independent of confounders (standardized β 0.37, P = 0.02). Reduced RFR might associate with the risk of preeclampsia and ESKD in kidney donors. Prospective studies should explore whether RFR is related to preeclampsia and whether BMI reduction before conception is of benefit to overweight female kidney donors during and after pregnancy.

5

There is a growing consensus that chronic kidney disease (CKD) patients should engage in regular exercise, but there is a lack of formal guidelines. In this report, we determined whether combined aerobic and resistance exercise would elicit superior physiological gains, in particular muscular strength, compared to aerobic training alone in non-dialysis CKD. Non-dialysis CKD patients stage 3b-5 were randomly allocated to aerobic exercise (AE, n=21; 9 males; median age 63years [IQR, 58-71]; median eGFR 24[IQR, 20-30] mL/min/1.73m2) or combined exercise (CE, n=20, 9 males, median age 63years [IQR, 51-69], median eGFR 27[IQR, 22-32] mL/min/1.73m2), preceded by a 6-week run in control period. Patients then underwent 12-weeks of supervised AE (treadmill, rowing or cycling exercise) or CE training (as AE plus leg extension and leg press exercise) performed 3x/week. Outcome assessments of knee extensor muscle strength, quadriceps muscle volume, exercise capacity and central haemodynamics were performed at baseline, following the 6-week control period and at the end of the intervention. AE and CE resulted in significant increases in knee extensor strength of 1619% (P=0.001) and 4837% (P<0.001) respectively, which were greater after CE (P=0.02). AE and CE resulted in 57% (P=0.04) and 97% (P<0.001) increases in quadriceps volume respectively (P<0.001) which was greater after CE (P=0.01). Both AE and CE increased distance walked in ISWT (2844m; P=0.01 and 3245m P=0.01) respectively. In non-dialysis CKD, the addition of resistance exercise to aerobic exercise confers greater increases in muscle mass and strength than aerobic exercise alone.

Concepts: Muscle, Knee, Cycling, Strength training, Weight training, Thigh, Extension, Exercise physiology

3

Animals living in desert environments are forced to survive despite severe heat, intense solar radiation, and both acute and chronic dehydration. These animals have evolved phenotypes that effectively address these environmental stressors. To begin to understand the ways in which the desert-adapted rodent P. eremicus survives, we performed an experiment where we subjected reproductively mature adults to 72 hours of water deprivation, during which they lost on average 23% of their body weight. The animals reacted via a series of changes in the kidney, which included modulating expression of genes responsible for reducing the rate of transcription and maintaining water and salt balance. Extracellular matrix turnover appeared to be decreased, and apoptosis was limited. Serum creatinine and other biomarkers of kidney injury were not elevated, which is different than the canonical human response, suggesting that changes in gene expression related to acute dehydration may effectively prohibit widespread kidney damage in the cactus mouse.

Concepts: DNA, Gene, Genetics, Gene expression, Evolution, Transcription, Molecular biology, RNA polymerase

3

Autosomal-dominant polycystic kidney disease is a common cause of end-stage renal disease, and no approved treatment is available in the US to slow disease progression. The mTOR signaling pathway is aberrantly activated in renal cysts, and, while mTOR inhibitors are highly effective in rodent models, clinical trials in ADPKD have been disappointing due to dose-limiting extra-renal side effects. Since mTOR is known to be regulated by nutrients and cellular energy status we hypothesized that dietary restriction may affect renal cyst growth. Here we show that reduced food intake (RFI) by 23% profoundly affects polycystic kidneys in an orthologous mouse model of ADPKD with a mosaic conditional knockout of PKD1. This mild level of RFI does not affect normal body weight gain, cause malnutrition or any other apparent side effects. RFI substantially slows disease progression: relative kidney weight increase was 41% vs. 151% in controls, proliferation of cyst-lining cells was 7.7% vs. 15.9% in controls. Mice on RFI diet maintained kidney function and did not progress to end-stage renal disease. The two major branches of mTORC1 signaling, S6 and 4EBP1, are both suppressed in cyst-lining cells by RFI suggesting that this dietary regimen may be more broadly effective than pharmacological mTOR inhibition with rapalogues which primarily affects the S6 branch. These results indicate that polycystic kidneys are exquisitely sensitive to minor reductions in nutrient supply or energy status. This study suggests that a mild decrease in food intake represents a potential therapeutic intervention to slow disease progression in ADPKD patients.

Concepts: Renal failure, Chronic kidney disease, Kidney, Nephrology, Erythropoietin, Nutrition, Polycystic kidney disease, Kidney diseases

2

Angiotensin (Ang) II is a major mediator of hypertension pathogenesis. In addition, there are well-documented differences in expression of the renin angiotensin system (RAS) components and Ang II responses between males and females, which may explain sex differences in blood pressure (BP) and hypertension epidemiology. We have previously shown that type 1A Angiotensin (AT1A) receptors in vascular smooth muscle cells (VSMCs) play a critical role in BP regulation and hypertension pathogenesis, but these studies were carried out in male mice. Therefore, the major goal of these studies is to examine the impact of VSMC AT11A receptors on BP and hypertension pathogenesis in female mice. We found that elimination of VSMC AT1A receptors in female mice caused a reduction (≈8 mmHg) in baseline BP without altering sodium sensitivity. The severity of Ang II-dependent hypertension was diminished particularly during the last two weeks of chronic Ang II infusion (≈33% reduction in BP) compared to controls without alterations in natriuresis during the first 5 days of Ang II. Female SMKO mice have enhanced urinary norepinephrine levels compared to controls. There was a virtually complete elimination of Ang II-dependent kidney hemodynamic responses with attenuation of acute vasoconstrictor responses in the systemic vasculature. These findings demonstrate that direct vascular actions of AT1A receptors play a prominent role in BP control and hypertension pathogenesis in female mice.

2

Several lines of evidence suggest that gut bacterial microbiota is altered in patients with chronic kidney disease (CKD), though the mechanism of which this dysbiosis takes place is not well understood. Recent studies delineated changes in gut microbiota in both CKD patients and experimental animal models using microarray chips. We present 16S ribosomal RNA gene sequencing of both stool pellets and small bowel contents of C57Bl/6J mice that underwent a remnant kidney model, and establish that changes in microbiota take place in the early gastrointestinal track. Increased intestinal urea concertation has been hypothesized as a leading contributor for dysbiotic changes in CKD. We show that urea transporters UT-A and UT-B mRNA are both expressed throughout the whole gastrointestinal track. The noted increase in intestinal urea concentration appears to be independent of urea transporters' expression. Urea supplementation in drinking water resulted in alteration in bacterial gut microbiota that is quite different than that seen in CKD. This indicates that increased intestinal urea concentration might not fully explain the CKD associated dysbiosis.

Concepts: Chronic kidney disease, Gene expression, Archaea, Bacteria, RNA, Ribosomal RNA, Ribosome, Digestive system