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Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown. Clonal hematopoiesis of indeterminate potential (CHIP) confers increased risk for several chronic diseases associated with aging. Here we sought to test whether CHIP increases the risk of AKI. In three population-based epidemiology cohorts, we found that CHIP was associated with a greater risk of incident AKI, which was more pronounced in patients with AKI requiring dialysis and in individuals with somatic mutations in genes other than DNMT3A, including mutations in TET2and JAK2. Mendelian randomization analyses supported a causal role for CHIP in promoting AKI. Non-DNMT3A-CHIP was also associated with a nonresolving pattern of injury in patients with AKI. To gain mechanistic insight, we evaluated the role of Tet2-CHIP and Jak2V617F-CHIP in two mouse models of AKI. In both models, CHIP was associated with more severe AKI, greater renal proinflammatory macrophage infiltration and greater post-AKI kidney fibrosis. In summary, this work establishes CHIP as a genetic mechanism conferring impaired kidney function recovery after AKI via an aberrant inflammatory response mediated by renal macrophages.

Following acute injury to the kidney, macrophages play an important role in recovery of functional and structural integrity, but organ fibrosis and progressive functional decline occur with incomplete recovery. Pro-resolving macrophages are characterized by increased cyclooxygenase 2 (COX-2) expression and this expression was selectively increased in kidney macrophages following injury and myeloid-specific COX-2 deletion inhibited recovery. Deletion of the myeloid prostaglandin E2 (PGE2) receptor, E-type prostanoid receptor 4 (EP4), mimicked effects seen with myeloid COX-2-/- deletion. PGE2-mediated EP4 activation induced expression of the transcription factor MafB in kidney macrophages, which upregulated anti-inflammatory genes and suppressed pro-inflammatory genes. Myeloid Mafb deletion recapitulated the effects seen with either myeloid COX-2 or EP4 deletion following acute kidney injury, with delayed recovery, persistent presence of pro-inflammatory kidney macrophages, and increased kidney fibrosis. Thus, our studies identified a previously unknown mechanism by which prostaglandins modulate macrophage phenotype following acute organ injury and provide new insight into mechanisms underlying detrimental kidney effects of non-steroidal anti-inflammatory drugs that inhibit cyclooxygenase activity.

The effect of in situ stress on the coal-breaking characteristics of water jets remains unclear, prohibiting the deep coalbed methane (CBM) development. Water jet coal-breaking experiments under different mean three-dimensional (3D) stresses and horizontal stress differences were carried out with a self-developed in situ stress simulator. When the mean 3D stress increased, coal changed from shear and tensile failure to shear failure, and the volume of the erosion pit first decreased rapidly and then slowly. Upon increasing the mean 3D stress from 0 to 10 MPa, the volume of the erosion pit decreased by 79.7%, and the specific energy consumption increased nearly five times. With an increase in horizontal stress difference, coal transitioned from shear failure to shear and tensile failure, resulting in a shear crack farther from the erosion pit. At a horizontal stress difference of 15 MPa, the volume of the erosion pit and specific energy consumption had maximum and minimum values, respectively. Consequently, constructing a higher horizontal stress difference helps improve the coal-breaking efficiency of water jets. This study could lay the foundation for applying water jet technology in deep coal seams.

Inadequate potassium (K+) consumption correlates with increased mortality and poor cardiovascular outcomes. Potassium effects on blood pressure have been described previously; however, whether or not low K+independently affects kidney disease progression remains unclear. Here, we demonstrate that dietary K+deficiency causes direct kidney injury. Effects depend on reduced blood K+and are kidney specific. In response to reduced K+, the channel Kir4.2 mediates altered proximal tubule (PT) basolateral K+flux, causing intracellular acidosis and activation of the enzyme glutaminase and the ammoniagenesis pathway. Deletion of either Kir4.2 or glutaminase protects from low-K+injury. Reduced K+also mediates injury and fibrosis in a model of aldosteronism. These results demonstrate that the PT epithelium, like the distal nephron, is K+sensitive, with reduced blood K+causing direct PT injury. Kir4.2 and glutaminase are essential mediators of this injury process, and we identify their potential for future targeting in the treatment of chronic kidney disease.

ABSTRACTMacroautophagy/autophagy protects against cellular stress. Renal sublethal injury-triggered tubular epithelial cell cycle arrest at G2/M is associated with interstitial fibrosis. However, the role of autophagy in renal fibrosis is elusive. Here, we hypothesized that autophagy activity in tubular epithelial cells is pivotal for inhibition of cell cycle G2/M arrest and subsequent fibrogenic response. In both renal epithelial cells stimulated by angiotensin II (AGT II) and the murine kidney after unilateral ureteral obstruction (UUO), we observed that occurrence of autophagy preceded increased production of COL1 (collagen, type I). Pharmacological enhancement of autophagy by rapamycin suppressed COL1 accumulation and renal fibrosis. In contrast, genetic ablation of autophagy by proximal tubular epithelial cell-specific deletion of Atg5, with reduction of the LC3-II protein level and degradation of SQSTM1/p62, showed marked cell cycle arrest at the G2/M phase, robust COL1 deposition, and severe interstitial fibrosis in a UUO model, as compared with wild-type mice. In vitro, AGT II exposure triggered autophagy preferentially in the G1/S phase, and increased COL1 expression in the G2/M phase in renal epithelial cells. Stimulation of Atg5-deficient primary proximal tubular cells with AGT II also resulted in elevated G2/M arrest and COL1 production. Pharmacological or genetic inhibition of autophagy increased AGT II-mediated G2/M arrest. Enhanced expression of ATG5, but not the autophagy-deficient ATG5 mutant K130R, rescued the G2/M arrest, suggesting the regulation of cell cycle progression by ATG5 is autophagy dependent. In conclusion, Atg5-mediated autophagy in proximal epithelial cells is a critical host-defense mechanism that prevents renal fibrosis by blocking G2/M arrest.

Heat shock protein 72 (HSP72) has been shown to attenuate unilateral ureteral obstruction–induced kidney fibrosis. It remains unknown whether HSP72 has direct effects on fibroblast proliferation in the renal fibrotic evolution. Herein, we first confirmed that increased HSP72 expression occurred in fibrotic human kidneys. Using three different animal models of kidney fibrosis, pharmacological down-regulation or genetic deletion of endogenous HSP72 expression exacerbated STAT3 phosphorylation, fibroblast proliferation, and tubulointerstitial fibrosis. In contrast, treatment with geranylgeranyl acetone, a specific inducer of HSP72, reduced phosphorylated STAT3 and protected animals from kidney fibrosis. In cultured renal interstitial fibroblasts, overexpression of HSP72 blocked transforming growth factor (TGF)-β1–induced cell activation and proliferation, as evidenced by inhibiting expression of α-smooth muscle actin, fibronectin, and collagen I/III, as well as by reducing cell numbers and DNA synthesis. Mechanical studies showed that overexpressed HSP72 attenuated TGF-β–induced phosphorylation and nuclear translocation of STAT3 and its downstream protein expression. However, siRNA knockdown of HSP72 increased TGF-β–induced STAT3 activity and fibroblast proliferation. Ectopic expression of a constitutively active STAT3 conferred resistance to HSP72 inhibition of fibroblast proliferation. Thus, HSP72 blocks fibroblast activation and proliferation in renal fibrosis via targeting the STAT3 pathway and may serve as a novel therapeutic agent for chronic kidney disease regardless of the etiology.

Background The prognostic value of pulmonary hypertension at the start of peritoneal dialysis (PD) in patient survival is unclear.Methods We conducted a retrospective study of incident patients who initiated PD therapy from January 2007 to December 2011, and followed up through June 2013. Pulmonary hypertension was defined as an estimated systolic pulmonary artery pressure (PAP) of ≥ 35 mm Hg using echocardiography. Clinical parameters and laboratory findings were compared between patients with and without pulmonary hypertension and a logistic regression model was elaborated. Patient outcomes (all-cause and cardiovascular mortality) were recorded during follow-up. Survival curves were constructed by the Kaplan-Meier method, and the influences of pulmonary hypertension on outcomes were analyzed by Cox regression models.Results Pulmonary hypertension was prevalent in 99 (16.0%) of the 618 patients studied. The independent risk factors for pulmonary hypertension were female (odds ratio [OR] = 2.12; 95% confidence interval [CI]: 1.29 – 3.46), left atrial diameter (OR = 1.15; 95% CI: 1.10 – 1.20), left ventricular ejection fraction (OR = 0.97; 95% CI: 0.95 – 0.99), and serum sodium (OR = 0.94; 95% CI: 0.89 – 0.99). Over a median follow-up of 29.4 months, 93 patients (15.0%) died, 59.1% of them due to cardiovascular disease. Kaplan-Meier survival analysis showed that patients with pulmonary hypertension had worse overall rates of survival and cardiovascular death-free survival than those without pulmonary hypertension. After multivariate adjustment, pulmonary hypertension was independently associated with increased risk for both all-cause and cardiovascular mortality, with hazard ratios (HRs) of 2.10 (95% CI: 1.35 – 3.27) and 2.60 (95% CI: 1.48 – 4.56), respectively.Conclusions The prevalence of pulmonary hypertension at the start of PD was common and associated with increased risk of both all-cause and cardiovascular mortality in incident PD patients.

In recent years, the water jet technology has become an important means for processing unconventional oil and gas resources. With the exploitation of resources to the deep development, the study of the fracture characteristics and failure modes of true triaxial water jet rock breaking is of major importance for the application of the water jet technology in deeper crustal levels. We selected three typical unconventional gas reservoirs, coal, sandstone, and shale, as samples for our rock-breaking experiments of water jet under true triaxial conditions. On the basis of the rock failure criterion considering triaxial stress, we establish the rock-breaking energy criterion of water jet under true triaxial conditions and study the rock-breaking mode of water jet under true triaxial conditions. Experimental results document that the true triaxial water jet rock-breaking energy criterion can predict the rock-breaking threshold pressure well. With the increase of triaxial stress, the breaking threshold pressure of coal, sandstone, and shale increased by 92, 38, and 37%, respectively. Under true triaxial conditions, the failure characteristics and failure modes of different rocks impacted by water jet differ significantly. The water wedge action of coal is weakened, the volume of the crushing pit was reduced by 90%, and the failure is mainly caused by the shear failure that is induced by jet pressure. Sandstone is still dominated by the denudation failure that is caused by jet, but the degree of destruction is weakened, and the volume of the crushing pit was reduced by 38%. The shale has changed from tensile failure that is dominated by stress waves to erosion pit failure that is dominated by shear action. The results of the study provide a reference for the application of the water jet technology for the exploitation of unconventional oil and gas resources in deeper crust levels.

Peritoneal dialysis–related peritonitis causes the denudation of mesothelial cells and, ultimately, membrane integrity alterations and peritoneal dysfunction. Because heat shock protein 72 (HSP72) confers protection against apoptosis and because autophagy mediates survival in response to cellular stresses, we examined whether autophagy contributes to HSP72-mediated cytoprotection in lipopolysaccharide (LPS)-induced peritonitis. Exposure of cultured peritoneal mesothelial cells to LPS resulted first in autophagy and later, apoptosis. Inhibition of autophagy by 3-methyladenine or Beclin-1 small-interfering RNA sensitized cells to apoptosis and abolished the antiapoptotic effect of HSP72, suggesting that autophagy activation acts as a prosurvival mechanism. Overexpression of HSP72 augmented autophagy through c-Jun N-terminal kinase (JNK) phosphorylation and Beclin-1 up-regulation. Suppression of JNK activity reversed HSP72-mediated Beclin-1 up-regulation and autophagy, indicating that HSP72-mediated autophagy is JNK dependent. In a rat model of LPS-associated peritonitis, autophagy occurred before apoptosis in peritoneum. Up-regulation of HSP72 by geranylgeranylacetone increased autophagy, inhibited apoptosis, and attenuated peritoneal injury, and these effects were blunted by down-regulation of HSP72 with quercetin. Additionally, blocking autophagy by chloroquine promoted apoptosis and aggravated LPS-associated peritoneal dysfunction. Thus, HSP72 protects peritoneum from LPS-induced mesothelial cells injury, at least in part by enhancing JNK activation–dependent autophagy and inhibiting apoptosis. These findings imply that HSP72 induction might be a potential therapy for peritonitis.

Horizontal wellbore fracturing technology is an effective method to stimulate reservoirs and increase energy production, such as gas, oil, and geothermy. The perforation layout parameters are the key parameters affecting the fracturing effect. To analyze the influence of perforation layout parameters on hydraulic fracture propagation and optimization of the perforation layout parameters, the stress surrounding the perforation is derived, key oriented points and effective oriented angles are defined, and effective oriented criteria are proposed. The principal stress direction angle can be divided into three stages as the distance from the fracturing hole increases: decreasing stage (tends to the connection direction of perforations), stable stage, and increasing stage (tends to the maximum horizontal ground stress direction). A common relationship between the perforation length, the initial angle, the ground stress difference, and the suitable oriented angle is obtained. The results will guide the field application of the above fracturing technologies.