Clinical Acute Kidney Injury and Histologic Acute Tubular-Interstitial Injury and Their Prognosis in Diabetic Nephropathy.

INTRODUCTION: Histologic acute tubular-interstitial injury (hATI) is often observed in patients with diabetic nephropathy (DN). This study aimed to determine the relationship between hATI and clinical acute kidney injury (cAKI) and evaluate significance of hATI in patients with DN. METHODS: Patients with biopsy-proven DN through 2003-2018 in our center were selected. The prevalence of hATI and its correlations with cAKI, tubular injury biomarkers, and serum creatinine were investigated. The renal survival rates and prognostic factors were analyzed by Kaplan-Meier curve and Cox regression model, respectively. RESULTS: Of 1,414 patients with DN, 70.4% were male, with a median age of 50.0 years. The incidences of cAKI and hATI were 8.6% and 57.8%, respectively. The severities of most hATI were mild (91.0%). The incidence of cAKI in those with hATI was only 12.2%. The incidences of cAKI positively correlated with the scores of hATI (Kendall r = 0.273, p < 0.001). The presence of hATI was related to rapid creatinine rise and increased tubular injury biomarkers although without cAKI. After adjusting for significant covariates, multivariate Cox models showed that patients with hATI alone were one and a half times more likely to develop ESRD (hazard ratio [HR]: 1.46; 95% CI, 1.05-2.02) than those without hATI or cAKI, and patients with hATI plus cAKI were 3 times more likely to develop ESRD (HR: 2.96; 95% CI, 1.85-4.72). CONCLUSION: Our findings indicated that hATI was common in patients with DN where the majorities were mild hATI and without cAKI. hATI was an independent risk factor of DN progression, regardless of episodes of cAKI.

Modeling of the transport, hygroscopic growth, and deposition of multi-component droplets in a simplified airway with realistic thermal boundary conditions.

Accurate predictions of the droplet transport, evolution, and deposition in human airways are critical for the quantitative analysis of the health risks due to the exposure to the airborne pollutant or virus transmission. The droplet/particle-vapor interaction, i.e., the evaporation or condensation of the multi-component droplet/particle, is one of the key mechanisms that need to be precisely modeled. Using a validated computational model, the transport, evaporation, hygroscopic growth, and deposition of multi-component droplets were simulated in a simplified airway geometry. A mucus-tissue layer is explicitly modeled in the airway geometry to describe mucus evaporation and heat transfer. Pulmonary flow and aerosol dynamics patterns associated with different inhalation flow rates are visualized and compared. Investigated variables include temperature distributions, relative humidity (RH) distributions, deposition efficiencies, droplet/particle distributions, and droplet growth ratio distributions. Numerical results indicate that the droplet/particle-vapor interaction and the heat and mass transfer of the mucus-tissue layer must be considered in the computational lung aerosol dynamics study, since they can significantly influence the precise predictions of the aerosol transport and deposition. Furthermore, the modeling framework in this study is ready to be expanded to predict transport dynamics of cough/sneeze droplets starting from their generation and transmission in the indoor environment to the deposition in the human respiratory system.

Angiotensin II induces calcium/calcineurin signaling and podocyte injury by downregulating microRNA-30 family members.

Angiotensin II (AngII) is capable of inducing calcium/calcineurin signaling and podocyte injury; however, the precise underlying mechanism is not well understood. Because we have previously demonstrated that microRNA-30s (miR-30s) inhibit calcium/calcineurin signaling in podocytes, we hypothesize that AngII may induce podocyte injury by downregulating miR-30s and thereby activating calcium/calcineurin signaling. To test this hypothesis, we used an AngII-induced podocyte injury mouse model. The mice were treated with AngII via infusion for 28 days, which resulted in hypertension, albuminuria, and glomerular damage. AngII treatment also resulted in a significant reduction of miR-30s and upregulation of calcium/calcineurin signaling components, including TRPC6, PPP3CA, PPP3CB, PPP3R1, and NFATC3, which are the known targets of miR-30s in podocytes. The delivery of miR-30a-expressing lentivirus to the podocytes on day 14 of the infusion ameliorated the AngII-induced podocyte and glomerular injury and attenuated the upregulation of the calcium/calcineurin signaling components. Similarly, treatment with losartan, which is an AngII receptor blocker, also prevented AngII-induced podocyte injury and calcium/calcineurin signaling activation. Notably, losartan was found to sustain miR-30 levels during AngII treatment both in vivo and in vitro. In conclusion, the effect of AngII on podocytes is in part mediated by miR-30s through calcium/calcineurin signaling, a novel mechanism underlying AngII-induced podocyte injury. KEY MESSAGES: • AngII infusion resulted in downregulation of miR-30s in podocytes. • Exogenous miR-30a delivery mitigated the glomerular and podocyte injuries induced by AngII. • Both miR-30a and losartan prevented AngII-induced activation of calcium-calcineurin signaling.

Increased miR-374b promotes cell proliferation and the production of aberrant glycosylated IgA1 in B cells of IgA nephropathy.

The number of B cells is increased and the O-glycans of IgA1 are incompletely galactosylated in IgA nephropathy (IgAN). Here we report that expression of phosphatase and tensin homolog (PTEN) and Cosmc is decreased in B cells, and correlates with B cell number and the aberrant glycosylation of IgA1 in IgAN. Patients with IgAN exhibit higher miR-374b in B cells compared to controls. We show that miR-374b targets PTEN and Cosmc by luciferase assays and western blot analysis. Inhibition of miR-374b increased PTEN and Cosmc expression, and prevented cell proliferation and aberrant glycosylation of IgA1, thus representing a new therapeutic approach for IgAN.