Qian, Qi

Abstract Hypoxia‐induced extracellular matrix (ECM) deposition is an important cause of renal fibrosis that is triggered by unknown mechanisms. Human epididymis secretory protein 4 (HE4) is a newly discovered key molecule that causes ECM deposition. We used the unilateral ureteral obstruction (UUO) mouse model to investigate the expression and mechanisms of HE4 in the pathogenesis of renal fibrosis. Results were confirmed in the HK2 cell line and in human donors of kidney tissue with chronic kidney disease. Hypoxia significantly increased HE4 in renal tubular epithelial cells. HE4 overexpression activated the NF‐κB pathway through the NF‐κB transcription‐activating group P65 by phosphorylation and nuclear translocation. NF‐κB upregulated tissue inhibitor metalloproteinases 1, which may inhibit ECM degradation through inhibition of matrix metallopeptidase 2 activity. Silencing HE4 inhibited hypoxia‐induced ECM deposition and alleviated fibrosis in UUO mice in vivo and blocked NF‐κB activation in vitro. Expression of HE4 in the tubulointerstitium was positively correlated with tubulointerstitial fibrosis in tissue samples from patients with chronic kidney disease. Our results suggest that hypoxia induces renal fibrosis by upregulating HE4 and activating the HIF‐1α/HE4/NF‐κB signaling pathway. Uncovering the molecular mechanisms and function of HE4 overexpression in hypoxia‐induced renal fibrosis will provide important insights into understanding renal fibrosis and antifibrotic strategies.

This study investigated the role of insulin-like growth factor-1/insulin-like growth factor-1 receptor (IGF-1/IGF-1R) in the genesis and progression of diabetic kidney disease (DKD) in a streptozotocin (STZ)-induced mouse diabetes model. We showed elevated IGF-1 expression in the DKD kidneys after 16 wk of diabetic onset. Intraperitoneal administration of IGF-1R inhibitor (glycogen synthase kinase-3β, GSK4529) from week 8 to week 16 postdiabetes induction ameliorated urinary albumin excretion and kidney histological changes due to diabetes, including amelioration of glomerulomegaly, inflammatory infiltration, and tubulointerstitial fibrosis. The GSK4529 treatment also attenuated alterations in renal tubular expression of E-cad and matrix protein fibronectin. Moreover, renal fibrosis in DKD (without treatment) was associated with Snail1 overexpression that was effectively prevented by IGF-1R inhibition. Further experiments in cultured renal epithelial cells (NRK) showed that IGF-1 silencing reproduced in vivo effects of IGF-1R inhibition with markedly attenuated Snail1 expression and near normalization of the Ecad1 and fibronectin expression pattern. Further Snail1 silencing prevented high-glucose-induced changes without affecting IGF-1 expression, consistent with Snail1 acting downstream to IGF-1. The antifibrotic effects were also shown with benazepril or insulin treatment but to a much lesser degree. In summary, in STZ-induced diabetic mice, activation of IGF-1 in diabetic kidneys induces fibrogenesis through Snail1 upregulation. The diabetes-related histological and functional changes, as well as fibrogenesis, can be attenuated by IGF-1/IGF-1R inhibition.

Abstract Background This study aimed to evaluate short-term and long-term mortalities in a cohort of unselected hospitalized patients with serum sodium concentration ([Na+]) variations within and outside of reference range. Methods All adult patients admitted to the Mayo Clinic, Rochester, MN, USA from January 2011 to December 2013 (n = 147358) were retrospectively screened. Unique patients admitted during the study period were examined. The main exposure was serum [Na+] variation. Outcome measures were hospital and 1-year all-cause mortalities. Results A total of 60944 patients, mean age 63 ± 17 years, were studied. On admission, 17% (n = 10066) and 1.4% (n = 852) had hypo- and hypernatremia, respectively. During the hospital stay, 11044 and 4128 developed hypo- and hypernatremia, respectively, accounting for 52.3 and 82.9% of the total hypo- and hypernatremic patients. Serum [Na+] variations of ≥6 mEq/L occurred in 40.6% (n = 24 740) of the 60 944 patients and were significantly associated with hospital and 1-year mortalities after adjusting potential confounders (including demographics, comorbidities, estimated glomerular filtration rate, admission serum [Na+], number of [Na+] measurements and length of hospital stay). Adjusted odds ratios for hospital and 1-year mortalities increased with increasing [Na+] variations in a dose-dependent manner, from 1.47 to 5.48 (all 95% confidence intervals >1.0). Moreover, in fully adjusted models, [Na+] variations (≥6 mEq/L) within the reference range (135–145 mEq/L) or borderline hypo- or hypernatremia (133–137 and 143–147 mEq/L, respectively) compared with 138–142 mEq/L were associated with increased hospital and 1-year mortalities. Conclusion In hospitalized adults, [Na+] fluctuation (≥6 mEq/L) irrespective of admission [Na+] and borderline hypo- or hypernatremia are independent predictors of progressively increasing short- and long-term mortality burdens.

ABSTRACTOur knowledge on sodium and water homeostasis and regulation continues to evolve. A considerable amount of new information in this area has emerged in recent years. This review summarizes existing and new literature and discusses complex multi‐organ effects of high‐salt and low‐water intake and role of arginine vasopressin in this process, as well as the potential clinical significance of non‐osmotic sodium storage pool and rhythmicity of urine sodium excretion. It has become clear that sodium and water dysregulation can exert profound effects on kidney and vascular health, far greater than previously recognized. Maladaptation to a combined high‐salt and low‐water intake can be linked to the growing epidemic of hypertension and chronic kidney disease.

Abstract Hypoxia plays an important role in the genesis and progression of renal fibrosis. The underlying mechanisms, however, have not been sufficiently elucidated. We examined the role of p53 in hypoxia-induced renal fibrosis in cell culture (human and rat renal tubular epithelial cells) and a mouse unilateral ureteral obstruction (UUO) model. Cell cycle of tubular cells was determined by flow cytometry, and the expression of profibrogenic factors was determined by RT-PCR, immunohistochemistry, and western blotting. Chromatin immunoprecipitation and luciferase reporter experiments were performed to explore the effect of HIF-1α on p53 expression. We showed that, in hypoxic tubular cells, p53 upregulation suppressed the expression of CDK1 and cyclins B1 and D1, leading to cell cycle (G2/M) arrest (or delay) and higher expression of TGF-β, CTGF, collagens, and fibronectin. p53 suppression by siRNA or by a specific p53 inhibitor (PIF-α) triggered opposite effects preventing the G2/M arrest and profibrotic changes. In vivo experiments in the UUO model revealed similar antifibrotic results following intraperitoneal administration of PIF-α (2.2 mg/kg). Using gain-of-function, loss-of-function, and luciferase assays, we further identified an HRE3 region on the p53 promoter as the HIF-1α-binding site. The HIF-1α–HRE3 binding resulted in a sharp transcriptional activation of p53. Collectively, we show the presence of a hypoxia-activated, p53-responsive profibrogenic pathway in the kidney. During hypoxia, p53 upregulation induced by HIF-1α suppresses cell cycle progression, leading to the accumulation of G2/M cells, and activates profibrotic TGF-β and CTGF-mediated signaling pathways, causing extracellular matrix production and renal fibrosis.

The popular modern diet, characterized by an excess of animal protein and salt but insufficient in fruits, vegetables and water, is a poor fit for human physiological and homeostatic regulatory systems. Sustained net acid and sodium retention, coupled with an insufficient intake of cardiovascular protective potassium-rich foods and hydration in the modern diet can give rise to debilitating chronic organ dysfunction and ultimately, mortality. This holds true, especially in our aging population who are already facing inevitable decline in organ functional reserve. Importantly, in most cases, despite the mismatch and adverse effects to multiple organ systems, plasma electrolyte and acid-base parameters can, on the surface, be maintained within a “normal” reference range, primarily by activating (often maximally activating) compensatory homeostatic mechanisms. These diet-induced effects can thus be clinically silent for decades. Embodied in the chronic corrective homeostatic processes, however, are real risks for multiorgan damage. According to the Dietary Guideline Advisory Committee (DGAC), half of American adults have one or more chronic diseases that are preventable with dietary modification. Here, homeostasis of body fluid acid-base, sodium, potassium and water is examined. Our current dietary habits and their required regulatory adaptation, maladaptation and relevant physiology and pathophysiology are discussed. A framework of dietary modifications to avoid a propensity for maladaptation and thus lowers the risks of common modern diseases (primary prevention) and minimizes the risk of chronic and age-related disease progression (secondary prevention) is emphasized. Although there are other variables at play, a key to restoring the all-important dietary potassium to sodium ratio is greater consumption of vegetables/fruits and adopting salt temperance. Dietary and nutritional optimization is an under-emphasized area of health care that has an enormous potential to temper the epidemics of prevalent chronic diseases in modern society and improve population health.