Accumulation of worn-out GBM material substantially contributes to mesangial matrix expansion in diabetic nephropathy
Thickening of the glomerular basement membrane (GBM) and expansion of the mesangial matrix are hallmarks of diabetic nephropathy (DN), generally considered to emerge from different sites of overproduction: GBM components from podocytes and mesangial matrix from mesangial cells. Reevaluation of 918 biopsies with DN revealed strong evidence that these mechanisms are connected to each other, wherein excess GBM components fail to undergo degradation and are deposited in the mesangium. These data do not exclude that mesangial cells also synthesize components that contribute to the accumulation of matrix in the mesangium. Light,...
Source: AJP: Renal Physiology - June 4, 2017 Category: Urology & Nephrology Authors: Kriz, W., Löwen, J., Federico, G., van den Born, J., Gröne, E., Gröne, H. J. Tags: RESEARCH ARTICLE Source Type: research
Negative regulation of Smad1 pathway and collagen IV expression by store-operated Ca2+ entry in glomerular mesangial cells
Collagen IV (Col IV) is a major component of expanded glomerular extracellular matrix in diabetic nephropathy and Smad1 is a key molecule regulating Col IV expression in mesangial cells (MCs). The present study was conducted to determine if Smad1 pathway and Col IV protein abundance were regulated by store-operated Ca2+ entry (SOCE). In cultured human MCs, pharmacological inhibition of SOCE significantly increased the total amount of Smad1 protein. Activation of SOCE blunted high-glucose-increased Smad1 protein content. Treatment of human MCs with ANG II at 1 µM for 15 min, high glucose for 3 days, or TGF-β1 at ...
Source: AJP: Renal Physiology - June 4, 2017 Category: Urology & Nephrology Authors: Wu, P., Ren, Y., Ma, Y., Wang, Y., Jiang, H., Chaudhari, S., Davis, M. E., Zuckerman, J. E., Ma, R. Tags: RESEARCH ARTICLE Source Type: research
Dynamic coupling between TRPV4 and Ca2+-activated SK1/3 and IK1 K+ channels plays a critical role in regulating the K+-secretory BK channel in kidney collecting duct cells
The large-conductance Ca2+-activated K+ channel, BK (KCNMA1), is expressed along the connecting tubule (CNT) and cortical collecting duct (CCD) where it underlies flow- and Ca2+-dependent K+ secretion. Its activity is partially under the control of the mechanosensitive transient receptor potential vanilloid type 4 (TRPV4) Ca2+-permeable channel. Recently, we identified three small-/intermediate-conductance Ca2+-activated K+ channels, SK1 (KCNN1), SK3 (KCNN3), and IK1 (KCNN4), with notably high Ca2+-binding affinities, that are expressed in CNT/CCD and may be regulated by TRPV4-mediated Ca2+ influx. The K+-secreting CCD mCC...
Source: AJP: Renal Physiology - June 1, 2017 Category: Urology & Nephrology Authors: Li, Y., Hu, H., Tian, J.-B., Zhu, M. X., ONeil, R. G. Tags: RAPID REPORT Source Type: research
ENaC activity in the cortical collecting duct of HK{alpha}1 H+,K+-ATPase knockout mice is uncoupled from Na+ intake
Modulation of the epithelial Na+ channel (ENaC) activity in the collecting duct (CD) is an important mechanism for normal Na+ homeostasis. ENaC activity is inversely related to dietary Na+ intake, in part due to inhibitory paracrine purinergic regulation. Evidence suggests that H+,K+-ATPase activity in the CD also influences Na+ excretion. We hypothesized that renal H+,K+-ATPases affect Na+ reabsorption by the CD by modulating ENaC activity. ENaC activity in HKα1 H+,K+-ATPase knockout (HKα1–/–) mice was uncoupled from Na+ intake. ENaC activity on a high-Na+ diet was greater in the HKα1–/...
Source: AJP: Renal Physiology - June 1, 2017 Category: Urology & Nephrology Authors: Mironova, E., Lynch, I. J., Berman, J. M., Gumz, M. L., Stockand, J. D., Wingo, C. S. Tags: RESEARCH ARTICLE Source Type: research
Hydrochlorothiazide treatment increases the abundance of the NaCl cotransporter in urinary extracellular vesicles of essential hypertensive patients
This study highlights that NCC1/2, NCC1–3, and pNCC1–3-T55/T60 are upregulated by hydrochlorothiazide, and the increase in NCC abundance in uEVs of essential hypertensive patients correlates with the blood pressure response to hydrochlorothiazide. (Source: AJP: Renal Physiology)
Source: AJP: Renal Physiology - June 1, 2017 Category: Urology & Nephrology Authors: Pathare, G., Tutakhel, O. A. Z., van der Wel, M. C., Shelton, L. M., Deinum, J., Lenders, J. W. M., Hoenderop, J. G. J., Bindels, R. J. M. Tags: RESEARCH ARTICLE Source Type: research
Antenatal betamethasone attenuates the angiotensin-(1-7)-Mas receptor-nitric oxide axis in isolated proximal tubule cells
We previously reported a sex-specific effect of antenatal treatment with betamethasone (Beta) on sodium (Na+) excretion in adult sheep whereby treated males but not females had an attenuated natriuretic response to angiotensin-(1–7) [Ang-(1–7)]. The present study determined the Na+ uptake and nitric oxide (NO) response to low-dose Ang-(1–7) (1 pM) in renal proximal tubule cells (RPTC) from adult male and female sheep antenatally exposed to Beta or vehicle. Data were expressed as percentage of basal uptake or area under the curve for Na+ or percentage of control for NO. Male Beta RPTC exhibited greater Na+...
Source: AJP: Renal Physiology - June 1, 2017 Category: Urology & Nephrology Authors: Su, Y., Bi, J., Pulgar, V. M., Chappell, M. C., Rose, J. C. Tags: RESEARCH ARTICLE Source Type: research
Salt supplementation ameliorates developmental kidney defects in COX-2-/- mice
Deficiency of cyclooxygenase-2 (COX-2) activity in the early postnatal period causes impairment of kidney development leading to kidney insufficiency. We hypothesize that impaired NaCl reabsorption during the first days of life is a substantial cause for nephrogenic defects observed in COX-2–/– mice and that salt supplementation corrects these defects. Daily injections of NaCl (0.8 mg·g–1·day–1) for the first 10 days after birth ameliorated impaired kidney development in COX-2–/– pups resulting in an increase in glomerular size and fewer immature superficial glomeruli. Howe...
Source: AJP: Renal Physiology - June 1, 2017 Category: Urology & Nephrology Authors: Slattery, P., Frölich, S., Goren, I., Nüsing, R. M. Tags: RESEARCH ARTICLE Source Type: research
Nitric oxide reduces paracellular resistance in rat thick ascending limbs by increasing Na+ and Cl- permeabilities
About 50% of the Na+ reabsorbed in thick ascending limbs traverses the paracellular pathway. Nitric oxide (NO) reduces the permselectivity of this pathway via cGMP, but its effects on absolute Na+ (PNa+) and Cl– (PCl–) permeabilities are unknown. To address this, we measured the effect of l-arginine (0.5 mmol/l; NO synthase substrate) and cGMP (0.5 mmol/l) on PNa+ and PCl– calculated from the transepithelial resistance (Rt) and PNa+/PCl– in medullary thick ascending limbs. Rt was 7,722 ± 1,554 ohm·cm in the control period and 6,318 ± 1,757 ohm·cm after l-arginine treatmen...
Source: AJP: Renal Physiology - June 1, 2017 Category: Urology & Nephrology Authors: Monzon, C. M., Occhipinti, R., Pignataro, O. P., Garvin, J. L. Tags: RESEARCH ARTICLE Source Type: research
How important is the {alpha}1-adrenoceptor in primate and rodent proximal urethra? Sex differences in the contribution of {alpha}1-adrenoceptor to urethral contractility
In conclusion, male mouse and marmoset proximal USM shows strong α1A- adrenoceptor-induced contractions and abundant α1A-adrenoceptor expression, whereas α1A-adrenoceptor-mediated mechanisms are much less important in females. The differential expression of α1-adrenoceptors in the proximal urethra may contribute to the higher incidence of urinary incontinence in women and obstructed voiding in men. (Source: AJP: Renal Physiology)
Source: AJP: Renal Physiology - June 1, 2017 Category: Urology & Nephrology Authors: Alexandre, E. C., de Oliveira, M. G., Campos, R., Kiguti, L. R., Calmasini, F. B., Silva, F. H., Grant, A. D., Yoshimura, N., Antunes, E. Tags: RESEARCH ARTICLE Source Type: research
Blocking peptides and molecular mimicry as treatment for kidney disease
Protein mimotopes, or blocking peptides, are small therapeutic peptides that prevent protein-protein interactions by selectively mimicking a native binding domain. Inexpensive technology facilitates straightforward design and production of blocking peptides in sufficient quantities to allow preventive and therapeutic trials in both in vitro and in vivo experimental disease models. The kidney is an ideal peptide target, since small molecules undergo rapid filtration and efficient bulk absorption by tubular epithelial cells. Because the half-life of peptides is markedly prolonged in the kidneys compared with the bloodstream,...
Source: AJP: Renal Physiology - June 1, 2017 Category: Urology & Nephrology Authors: Havasi, A., Lu, W., Cohen, H. T., Beck, L., Wang, Z., Igwebuike, C., Borkan, S. C. Tags: REVIEW Source Type: research
Effect of diuretics on renal tubular transport of calcium and magnesium
Calcium (Ca2+) and Magnesium (Mg2+) reabsorption along the renal tubule is dependent on distinct trans- and paracellular pathways. Our understanding of the molecular machinery involved is increasing. Ca2+ and Mg2+ reclamation in kidney is dependent on a diverse array of proteins, which are important for both forming divalent cation-permeable pores and channels, but also for generating the necessary driving forces for Ca2+ and Mg2+ transport. Alterations in these molecular constituents can have profound effects on tubular Ca2+ and Mg2+ handling. Diuretics are used to treat a large range of clinical conditions, but most comm...
Source: AJP: Renal Physiology - June 1, 2017 Category: Urology & Nephrology Authors: Alexander, R. T., Dimke, H. Tags: REVIEW Source Type: research
U-shaped relationship between serum uric acid levels and intrarenal hemodynamic parameters in healthy subjects
Hyperuricemia has been reported to affect renal hemodynamics. In a recent study, both low and high levels of serum uric acid (SUA) were found to be associated with loss of kidney function. The goal of this study was to evaluate the relationship between SUA levels and intrarenal hemodynamic parameters in healthy subjects, using plasma clearance of para-aminohippurate (CPAH) and inulin (Cin). Renal and glomerular hemodynamics were evaluated by simultaneous measurements of CPAH and Cin in 48 healthy subjects (54.6 ± 13.4 yr). Intrarenal hemodynamic parameters, including efferent and afferent (Ra) arteriolar resistance,...
Source: AJP: Renal Physiology - June 1, 2017 Category: Urology & Nephrology Authors: Uedono, H., Tsuda, A., Ishimura, E., Nakatani, S., Kurajoh, M., Mori, K., Uchida, J., Emoto, M., Nakatani, T., Inaba, M. Tags: RESEARCH ARTICLE Source Type: research
Extracellular microRNA signature in chronic kidney disease
In this study we characterized the circulating and urinary miRNA pattern associated with reduced glomerular filtration rate, using Affymetrix GeneChip miR 4.0 in 28 patients with chronic kidney disease (CKD). Top miRNA discoveries from the human studies were validated in an Alb/TGFβ mouse model of CKD, and in rat renal proximal tubular cells (NRK52E) exposed to TGFβ1. Plasma and urinary levels of procollagen III N-terminal propeptide and collagen IV were elevated in patients with decreased estimated glomerular filtration rate (eGFR). Expression of 384 urinary and 266 circulatory miRNAs were significantly differen...
Source: AJP: Renal Physiology - June 1, 2017 Category: Urology & Nephrology Authors: Muralidharan, J., Ramezani, A., Hubal, M., Knoblach, S., Shrivastav, S., Karandish, S., Scott, R., Maxwell, N., Ozturk, S., Beddhu, S., Kopp, J. B., Raj, D. S. Tags: RESEARCH ARTICLE Source Type: research
Knockdown of Add3 impairs the myogenic response of renal afferent arterioles and middle cerebral arteries
We have reported that the myogenic response of the renal afferent arteriole (Af-art) and middle cerebral artery (MCA) and autoregulation of renal and cerebral blood flow are impaired in Fawn-Hooded Hypertensive (FHH) rats. Transfer of a region of chromosome 1 containing -adducin (Add3) from the Brown Norway rat rescued the vascular dysfunction and the development of renal disease. To examine whether Add3 is a viable candidate gene altering renal and cerebral hemodynamics in FHH rats, we knocked down the expression of Add3 in rat Af-arts and MCAs cultured for 36-h using a 27-mer Dicer-substrate short interfering RNA (DsiRNA...
Source: AJP: Renal Physiology - June 1, 2017 Category: Urology & Nephrology Authors: Fan, F., Pabbidi, M. R., Ge, Y., Li, L., Wang, S., Mims, P. N., Roman, R. J. Tags: RESEARCH ARTICLE Source Type: research
Exosome production and its regulation of EGFR during wound healing in renal tubular cells
In this study, we examined the relationship between exosome production and EGFR activation and the potential role of exosome in wound healing. EGFR activation occurred shortly after scratch wounding in renal tubular cells. Wound repair after scratching was significantly promoted by EGF and suppressed by EGFR inhibitor gefitinib. Interestingly, scratch wounding induced a significant increase of exosome production. The exosome production was decreased by EGF and increased by gefitinib, suggesting a suppressive role of EGFR signaling in exosome production. Conversely, inhibition of exosome release by GW4869 and manumycin A ma...
Source: AJP: Renal Physiology - June 1, 2017 Category: Urology & Nephrology Authors: Zhou, X., Zhang, W., Yao, Q., Zhang, H., Dong, G., Zhang, M., Liu, Y., Chen, J.-K., Dong, Z. Tags: RESEARCH ARTICLE Source Type: research
