American journal of physiology. Renal physiology
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Am. J. Physiol. Renal Physiol. · Jun 2019
Observational StudyElevated serum anion gap in adults with moderate chronic kidney disease increases risk for progression to end-stage renal disease.
Acid retention associated with reduced glomerular filtration rate (GFR) exacerbates nephropathy progression in partial nephrectomy models of chronic kidney disease (CKD) and might be reflected in patients with CKD with reduced estimated GFR (eGFR) by increased anion gap (AG). We explored the presence of AG and its association with CKD in 14,924 adults aged ≥20 yr with eGFR ≥ 15 ml·min-1·1.73 m-2 enrolled in the National Health and Nutrition Examination Survey III, 1988-1994, using multivariable regression analysis. The model was adjusted for sociodemographic characteristics, diabetes, and hypertension. ⋯ During followup, 9.2% of adults with moderate CKD developed ESRD. Those with AG in the highest tertile had a higher risk of ESRD after adjusting for covariates in a frailty model [relative hazard (95% confidence interval) for traditional AG: 1.76 (1.16-2.32)] compared with those in the middle tertile. The data suggest that high AG, even after adjusting for serum bicarbonate, is a contributing acid-base mechanism to CKD progression in adults with moderate chronic kidney disease.
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Am. J. Physiol. Renal Physiol. · Dec 2018
Periostin overexpression in collecting ducts accelerates renal cyst growth and fibrosis in polycystic kidney disease.
In polycystic kidney disease (PKD), persistent activation of cell proliferation and matrix production contributes to cyst growth and fibrosis, leading to progressive deterioration of renal function. Previously, we showed that periostin, a matricellular protein involved in tissue repair, is overexpressed by cystic epithelial cells of PKD kidneys. Periostin binds αVβ3-integrins and activates integrin-linked kinase (ILK), leading to Akt/mammalian target of rapamycin (mTOR)-mediated proliferation of human PKD cells. ⋯ These pathological changes were accompanied by increased renal expression of vimentin, α-smooth muscle actin, and type I collagen. We also found that periostin increased gene expression of pathways involved in repair, including integrin and growth factor signaling and ECM production, and it stimulated focal adhesion kinase, Rho GTPase, cytoskeletal reorganization, and migration of PKD cells. These results suggest that periostin stimulates signaling pathways involved in an abnormal tissue repair process that contributes to cyst growth and fibrosis in PKD.
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Am. J. Physiol. Renal Physiol. · Nov 2018
Multiparametric MRI detects longitudinal evolution of folic acid-induced nephropathy in mice.
The rodent model of folic acid (FA)-induced acute kidney injury (AKI) provides a useful model for studying human AKI, but little is known about longitudinal changes in renal hemodynamics and evolution of renal fibrosis in vivo. In this work, we aimed to longitudinally assess renal structural and functional changes using multiparametric magnetic resonance imaging (MRI). Ten adult mice were injected with FA, after which a multiparametric MRI was used to measure kidney volume, hypoxia index R2*, magnetization transfer ratio (MTR), perfusion, T1, and glomerular filtration rate (GFR) at 2 wk posttreatment. ⋯ Trichrome staining revealed patchy necrosis and mild interstitial fibrosis at 2 wk, which exacerbated at 4 wk. MTR detected increased fibrosis at 4 wk. In conclusion, multiparametric MRI captured the longitudinal progression in kidney damage evolving within the first month after treatment with folic acid and may provide a useful tool for assessment of therapeutic strategies.
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Am. J. Physiol. Renal Physiol. · Nov 2018
In vivo evidence for an interplay of FGF23/Klotho/PTH axis on the phosphate handling in renal proximal tubules.
Phosphate homeostasis is primarily maintained in the renal proximal tubules, where the expression of sodium/phosphate cotransporters (Npt2a and Npt2c) is modified by the endocrine actions of both fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH). However, the specific contribution of each regulatory pathway in the proximal tubules has not been fully elucidated in vivo. We have previously demonstrated that proximal tubule-specific deletion of the FGF23 coreceptor Klotho results in mild hyperphosphatemia with little to no change in serum levels of FGF23, 1,25(OH)2D3, and PTH. ⋯ While serum calcium was normal, 1,25(OH)2D3 levels were significantly decreased, leading to extremely high levels of PTH. Collectively, mice with a deletion of PTH1R alone in proximal tubules results in only minor changes in phosphate regulation, whereas deletion of both PTH1R and Klotho leads to a severe disturbance, including hyperphosphatemia with increased sodium/phosphate cotransporter expression in BBM. These results suggest an important interplay between the PTH/PTH1R and FGF23/Klotho pathways to affect renal phosphate handling in the proximal tubules.
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Am. J. Physiol. Renal Physiol. · Oct 2018
Prevention of the progression of renal injury in diabetic rodent models with preexisting renal disease with chronic endothelin A receptor blockade.
The endothelin (ET) system has emerged as a therapeutic target for the treatment of diabetic nephropathy (DN). The present study examined whether chronic endothelin A (ETA) receptor blockade with atrasentan prevents the progression of renal injury in two models of DN with preexisting renal disease that exhibit an increased renal ET-1 system compared with nondiabetic rats: streptozotocin-treated Dahl salt-sensitive (STZ-SS) and type 2 diabetic nephropathy (T2DN) rats. Nine week-old SS rats were treated with (STZ; 50 mg/kg ip) to induce diabetes. ⋯ In contrast to the STZ-SS study, atrasentan had no effect on MAP or proteinuria in T2DN rats. However, treatment with atrasentan significantly decreased glomerular injury and renal fibrosis and prevented the decline in renal function in T2DN rats. These data indicate that chronic ETA blockade produces advantageous changes in renal hemodynamics that slow the progression of renal disease and also reduces renal histopathology in the absence of reducing arterial pressure and proteinuria.