Organ Protection by Caloric Restriction Depends on Activation of the De Novo NAD+ Synthesis Pathway.

SIGNIFICANCE STATEMENT: AKI is a major clinical complication leading to high mortality, but intensive research over the past decades has not led to targeted preventive or therapeutic measures. In rodent models, caloric restriction (CR) and transient hypoxia significantly prevent AKI and a recent comparative transcriptome analysis of murine kidneys identified kynureninase (KYNU) as a shared downstream target. The present work shows that KYNU strongly contributes to CR-mediated protection as a key player in the de novo nicotinamide adenine dinucleotide biosynthesis pathway. Importantly, the link between CR and NAD+ biosynthesis could be recapitulated in a human cohort. BACKGROUND: Clinical practice lacks strategies to treat AKI. Interestingly, preconditioning by hypoxia and caloric restriction (CR) is highly protective in rodent AKI models. However, the underlying molecular mechanisms of this process are unknown. METHODS: Kynureninase (KYNU) knockout mice were generated by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and comparative transcriptome, proteome and metabolite analyses of murine kidneys pre- and post-ischemia-reperfusion injury in the context of CR or ad libitum diet were performed. In addition, acetyl-lysin enrichment and mass spectrometry were used to assess protein acetylation. RESULTS: We identified KYNU as a downstream target of CR and show that KYNU strongly contributes to the protective effect of CR. The KYNU-dependent de novo nicotinamide adenine dinucleotide (NAD+) biosynthesis pathway is necessary for CR-associated maintenance of NAD+ levels. This finding is associated with reduced protein acetylation in CR-treated animals, specifically affecting enzymes in energy metabolism. Importantly, the effect of CR on de novo NAD+ biosynthesis pathway metabolites can be recapitulated in humans. CONCLUSIONS: CR induces the de novo NAD+ synthesis pathway in the context of IRI and is essential for its full nephroprotective potential. Differential protein acetylation may be the molecular mechanism underlying the relationship of NAD+, CR, and nephroprotection.

Mechanisms of Caloric Restriction-Mediated Stress-Resistance in Acute Kidney Injury.

Caloric restriction (CR)-mediated organ protection has been shown to be extremely efficient in rodent models of acute kidney injury (AKI). Limited understanding of the underlying mechanisms paired with a risk of malnourishment and feasibility problems has hindered the translation of this immense potential to the patient setting. In this mini-review, the current mechanistic concepts of CR-mediated stress-resistance as potential key targets for renal protection in AKI will be highlighted.

The kidney in hantavirus infection-epidemiology, virology, pathophysiology, clinical presentation, diagnosis and management.

Hantavirus-induced diseases are emerging zoonoses with endemic appearances and frequent outbreaks in different parts of the world. In humans, hantaviral pathology is characterized by the disruption of the endothelial cell barrier followed by increased capillary permeability, thrombocytopenia due to platelet activation/depletion and an overactive immune response. Genetic vulnerability due to certain human leukocyte antigen haplotypes is associated with disease severity. Typically, two different hantavirus-caused clinical syndromes have been reported: hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). The primarily affected vascular beds differ in these two entities: renal medullary capillaries in HFRS caused by Old World hantaviruses and pulmonary capillaries in HCPS caused by New World hantaviruses. Disease severity in HFRS ranges from mild, e.g. Puumala virus-associated nephropathia epidemica, to moderate, e.g. Hantaan or Dobrava virus infections. HCPS leads to a severe acute respiratory distress syndrome with high mortality rates. Due to novel insights into organ tropism, hantavirus-associated pathophysiology and overlapping clinical features, HFRS and HCPS are believed to be interconnected syndromes frequently involving the kidneys. As there are no specific antiviral treatments or vaccines approved in Europe or the USA, only preventive measures and public awareness may minimize the risk of hantavirus infection. Treatment remains primarily supportive and, depending on disease severity, more invasive measures (e.g., renal replacement therapy, mechanical ventilation and extracorporeal membrane oxygenation) are needed.

A systematic analysis of diet-induced nephroprotection reveals overlapping changes in cysteine catabolism.

Caloric Restriction (CR) extends lifespan and augments cellular stress-resistance from yeast to primates, making CR an attractive strategy for organ protection in the clinic. Translation of CR to patients is complex, due to problems regarding adherence, feasibility, and safety concerns in frail patients. Novel tailored dietary regimens, which modulate the dietary composition of macro- and micronutrients rather than reducing calorie intake promise similar protective effects and increased translatability. However, a direct head-to-head comparison to identify the most potent approach for organ protection, as well as overlapping metabolic consequences have not been performed. We systematically analyzed six dietary preconditioning protocols - fasting mimicking diet (FMD), ketogenic diet (KD), dietary restriction of branched chained amino acids (BCAA), two dietary regimens restricting sulfur-containing amino acids (SR80/100) and CR - in a rodent model of renal ischemia-reperfusion injury (IRI) to quantify diet-induced resilience in kidneys. Of the administered diets, FMD, SR80/100 and CR efficiently protect from kidney damage after IRI. Interestingly, these approaches show overlapping changes in oxidative and hydrogen sulfide (H2S)-dependent cysteine catabolism as a potential common mechanism of organ protection.

CALINCA-A Novel Pipeline for the Identification of lncRNAs in Podocyte Disease.

Diseases of the renal filtration unit-the glomerulus-are the most common cause of chronic kidney disease. Podocytes are the pivotal cell type for the function of this filter and focal-segmental glomerulosclerosis (FSGS) is a classic example of a podocytopathy leading to proteinuria and glomerular scarring. Currently, no targeted treatment of FSGS is available. This lack of therapeutic strategies is explained by a limited understanding of the defects in podocyte cell biology leading to FSGS. To date, most studies in the field have focused on protein-coding genes and their gene products. However, more than 80% of all transcripts produced by mammalian cells are actually non-coding. Here, long non-coding RNAs (lncRNAs) are a relatively novel class of transcripts and have not been systematically studied in FSGS to date. The appropriate tools to facilitate lncRNA research for the renal scientific community are urgently required due to a row of challenges compared to classical analysis pipelines optimized for coding RNA expression analysis. Here, we present the bioinformatic pipeline CALINCA as a solution for this problem. CALINCA automatically analyzes datasets from murine FSGS models and quantifies both annotated and de novo assembled lncRNAs. In addition, the tool provides in-depth information on podocyte specificity of these lncRNAs, as well as evolutionary conservation and expression in human datasets making this pipeline a crucial basis to lncRNA studies in FSGS.

Development and design of the Hantavirus registry - HantaReg - for epidemiological studies, outbreaks and clinical studies on hantavirus disease.

BACKGROUND: Frequent outbreaks around the globe and endemic appearance in different parts of the world emphasize the substantial risk of hantavirus diseases. Increasing incidence rates, trends of changing distribution of hantavirus species and new insights into clinical courses of hantavirus diseases call for multinational surveillance. Furthermore, evidence-based guidelines for the management of hantavirus diseases and scoring systems, which allow stratification of patients into risk categories, are lacking. METHODS: Hantavirus registry (HantaReg) is a novel registry platform facilitating multinational research of hantavirus-caused diseases, such as haemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). HantaReg provides an electronic case report form and uses the General Data Protection Regulation compliant platform clinicalsurveys.net, which can be accessed from any internet browser in the world. Having a modular structure, the registry platform is designed to display or hide questions and items according to the documented case (e.g. patient with HFRS versus HCPS) to facilitate fast, but standardized, data entry. Information categories documented in HantaReg are demographics, pre-existing diseases, clinical presentation, diagnostic and therapeutic approaches, as well as outcome. CONCLUSIONS: HantaReg is a novel, ready-to-use platform for clinical and epidemiological studies on hantavirus diseases and facilitates the documentation of the disease course associated with hantavirus infections. HantaReg is expected to promote international collaboration and contributes to improving patient care through the analysis of diagnostic and treatment pathways for hantavirus diseases, providing evidence for robust treatment recommendations. Moreover, HantaReg enables the development of prognosis-indicating scoring systems for patients with hantavirus disease.