Diabetic nephropathy (DN) is associated with an increased morbidity and mortality, resulting in elevated cost for public health systems. DN is the main cause of chronic kidney disease (CKD) and its incidence increases the number of patients that develop the end-stage renal disease (ESRD). There are growing epidemiological and preclinical evidence about the close relationship between inflammatory response and the occurrence and progression of DN. Several anti-inflammatory strategies targeting specific inflammatory mediators (cell adhesion molecules, chemokines and cytokines) and intracellular signaling pathways have shown beneficial effects in experimental models of DN, decreasing proteinuria and renal lesions. A number of inflammatory molecules have been shown useful to identify diabetic patients at high risk of developing renal complications. In this review, we focus on the key role of inflammation in the genesis and progression of DN, with a special interest in effector molecules and activated intracellular pathways leading to renal damage, as well as a comprehensive update of new therapeutic strategies targeting inflammation to prevent and/or retard renal injury.

Chronic kidney disease (CKD) is one of the fastest-growing causes of death and is predicted to become by 2040 the fifth global cause of death. CKD is characterized by increased oxidative stress and chronic inflammation. However, therapies to slow or prevent CKD progression remain an unmet need. Nrf2 (nuclear factor erythroid 2-related factor 2) is a transcription factor that plays a key role in protection against oxidative stress and regulation of the inflammatory response. Consequently, the use of compounds targeting Nrf2 has generated growing interest for nephrologists. Pre-clinical and clinical studies have demonstrated that Nrf2-inducing strategies prevent CKD progression and protect from acute kidney injury (AKI). In this article, we review current knowledge on the protective mechanisms mediated by Nrf2 against kidney injury, novel therapeutic strategies to induce Nrf2 activation, and the status of ongoing clinical trials targeting Nrf2 in renal diseases.

Glomerular hematuria is a cardinal symptom of renal disease. Glomerular hematuria may be classified as microhematuria or macrohematuria according to the number of red blood cells in urine. Recent evidence suggests a pathological role of persistent glomerular microhematuria in the progression of renal disease. Moreover, gross hematuria, or macrohematuria, promotes acute kidney injury (AKI), with subsequent impairment of renal function in a high proportion of patients. In this pathological context, hemoglobin, heme, or iron released from red blood cells in the urinary space may cause direct tubular cell injury, oxidative stress, pro-inflammatory cytokine production, and further monocyte/macrophage recruitment. The aim of this manuscript is to review the role of glomerular hematuria in kidney injury, the role of inflammation as cause and consequence of glomerular hematuria, and to discuss novel therapies to combat hematuria.

Massive intravascular hemolysis occurs not unfrequently in many clinical conditions. Breakdown of erythrocytes promotes the accumulation of heme-derivates in the kidney, increasing oxidative stress and cell death, thus promoting acute kidney injury (AKI). NADPH oxidase 4 (Nox4) is a major source of reactive oxygen species (ROS) in the kidney, however it is unknown the role of Nox4 in hemolysis and whether inhibition of this enzyme may protect from heme-mediated injury. To answer these questions, we elicited intravascular hemolysis in wild type and Nox4 knockout mice. We also evaluated whether nephrotoxic effects of heme may be reduced by using Nox4 siRNA and pharmacologic inhibition with GKT137831, a Nox4 inhibitor, both in vivo and in cultured renal cells. Our results showed that induction of massive hemolysis elicited AKI characterized by loss of renal function, morphological alterations of the tubular epithelium and podocytes, oxidative stress, inflammation, mitochondrial dysfunction, blockade of autophagy and cell death. These pathological effects were significantly prevented in Nox4-deficient mice and in animals treated with GKT137831. In vitro studies showed that Nox4 disruption by specific siRNAs or Nox4 inhibitors declined heme-mediated ROS production and cell death. Our data identify Nox4 as a key enzyme involved in intravascular hemolysis-induced AKI. Thus, Nox4 inhibition may be a potential therapeutic approach to prevent renal damage in patients with severe hemolytic crisis.

Background/Objectives: Acute kidney injury (AKI) remains an unsolved medical problem due to the lack of effective treatments, high mortality, and increased susceptibility to progression to chronic kidney disease (CKD), especially in the elderly. Cellular senescence has been described in AKI, CKD, and aging and has been proposed as a promising therapeutic target. The senolytic drug combination of dasatinib plus quercetin (D&Q) is beneficial in some pathological conditions, including experimental CKD, but there are no data for AKI. Methods: The effect of D&Q combination was tested in folic acid-induced nephrotoxicity (FAN-AKI), a murine AKI model. Results: D&Q pretreatment did not prevent renal dysfunction in the acute phase of FAN-AKI, as determined by serum creatinine and BUN levels at 48 h. Moreover, gene expression of the kidney damage biomarkers Lcn2 and Havcr1, the Cdkn1a gene, which encodes p21, and some genes encoding components of the senescent cell secretome were significantly increased in response to D&Q treatment. The number of senescent p21-positive cells in injured kidneys was similar in untreated or D&Q-treated FAN mice. In addition, D&Q did not prevent the downregulation of the antiaging factor Klotho in damaged kidneys. Conclusions: D&Q treatment was not protective in FAN-AKI, exacerbating some deleterious responses. These results suggest caution when exploring the clinical translation of D&Q senolytic activity.

There is a pressing need to develop new strategies for enhancing health in the elderly and preventing the rise in age-related diseases. Calorie restriction without malnutrition (CR) stands among the different antiaging interventions. Lifelong CR leads to increased expression and activity of plasma membrane CYB5R3, and male mice overexpressing CYB5R3 exhibit some beneficial adaptations that are also seen with CR. However, the mechanisms involved in both interventions could be independent since key aspects of energy metabolism and tissue lipid profile do not coincide, and many of the changes induced by CR in mitochondrial abundance and dynamics in the liver and skeletal muscle could be counteracted by CYB5R3 overexpression. In this study, we sought to elucidate the impact of CR on key markers of metabolic status, mitochondrial function, and pro-oxidant/antioxidant balance in transgenic (TG) female mice overexpressing CYB5R3 compared to their WT littermates. In females fed ad libitum, CYB5R3 overexpression decreased fat mass, led to a preferred utilization of fatty acids as an energy source, upregulated key antioxidant enzymes, and boosted respiration both in skeletal muscle and liver mitochondria, supporting that CYB5R3 overexpression is phenotypic closer to CR in females than in males. Whereas some markers of mitochondrial biogenesis and dynamics were found decreased in TG females on CR, as also found for the levels of Estrogen Receptor α, mitochondrial abundance and activity were maintained both in skeletal muscle and in liver. Our results reveal overlapping metabolic adaptations resulting from the overexpression of CYB5R3 and CR in females, but a specific crosstalk occurs when both interventions are combined, differing from the adaptations observed in TG males.