In December 2019, a novel coronavirus was isolated from the respiratory epithelium of patients with unexplained pneumonia in Wuhan, China. This pathogen, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes a pathogenic condition that has been termed coronavirus disease 2019 (COVID-19) and has reached pandemic proportions. As of 17 September 2020, more than 30 million confirmed SARS-CoV-2 infections have been reported in 204 different countries, claiming more than 1 million lives worldwide. Accumulating evidence suggests that SARS-CoV-2 infection can lead to a variety of clinical conditions, ranging from asymptomatic to life-threatening cases. In the early stages of the disease, most patients experience mild clinical symptoms, including a high fever and dry cough. However, 20% of patients rapidly progress to severe illness characterized by atypical interstitial bilateral pneumonia, acute respiratory distress syndrome and multiorgan dysfunction. Almost 10% of these critically ill patients subsequently die. Insights into the pathogenic mechanisms underlying SARS-CoV-2 infection and COVID-19 progression are emerging and highlight the critical role of the immunological hyper-response — characterized by widespread endothelial damage, complement-induced blood clotting and systemic microangiopathy — in disease exacerbation. These insights may aid the identification of new or existing therapeutic interventions to limit the progression of early disease and treat severe cases.

Here, we review the most recent findings on the effects of SARS-CoV-2 infection on kidney diseases, including acute kidney injury, and examine the potential effects of ARBs on the outcomes of patients with COVID-19. Lastly, we discuss the clinical management of COVID-19 patients with existing chronic renal disorders, particularly those in dialysis and with kidney transplants.

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Sirtuins belong to an evolutionarily conserved family of NAD-dependent deacetylases that share multiple cellular functions related to proliferation, DNA repair, mitochondrial energy homeostasis, and antioxidant activity. Mammalians express seven sirtuins (SIRT1-7) that are localized in different subcellular compartments. Changes in sirtuin expression are critical in several diseases, including metabolic syndrome, diabetes, cancer, and aging. In the kidney, the most widely studied sirtuin is SIRT1, which exerts cytoprotective effects by inhibiting cell apoptosis, inflammation, and fibrosis together with SIRT3, a crucial metabolic sensor that regulates ATP generation and mitochondrial adaptive response to stress. Here, we provide an overview of the biologic effects of sirtuins and the molecular targets thereof regulating renal physiology. This review also details progress made in understanding the effect of sirtuins in the pathophysiology of chronic and acute kidney diseases, highlighting the key role of SIRT1, SIRT3, and now SIRT6 as potential therapeutic targets. In this context, the current pharmacologic approaches to enhancing the activity of SIRT1 and SIRT3 will be discussed.

Genetic studies of hereditary forms of nephrotic syndrome have identified several proteins that are involved in regulating the permselective properties of the glomerular filtration system. Further extensive research has elucidated the complex molecular basis of the glomerular filtration barrier and clearly established the pivotal role of podocytes in the pathophysiology of glomerular diseases. Podocyte architecture is centred on focal adhesions and slit diaphragms - multiprotein signalling hubs that regulate cell morphology and function. A highly interconnected actin cytoskeleton enables podocytes to adapt in order to accommodate environmental changes and maintain an intact glomerular filtration barrier. Actin-based endocytosis has now emerged as a regulator of podocyte integrity, providing an impetus for understanding the precise mechanisms that underlie the steady-state control of focal adhesion and slit diaphragm components. This Review outlines the role of actin dynamics and endocytosis in podocyte biology, and discusses how molecular heterogeneity in glomerular disorders could be exploited to deliver more rational therapeutic interventions, paving the way for targeted medicine in nephrology.

Mesenchymal stromal cells (MSCs) are renoprotective and drive regeneration following injury, although cellular targets of such an effect are still ill-defined. Here, we show that human umbilical cord (UC)-MSCs transplanted into mice stimulate tubular cells to regain mitochondrial mass and function, associated with enhanced microtubule-rich projections that appear to mediate mitochondrial trafficking to create a reparative dialogue among adjacent tubular cells. Treatment with UC-MSCs in mice with cisplatin-induced acute kidney injury (AKI) regulates mitochondrial biogenesis in proximal tubuli by enhancing PGC1α expression, NAD+ biosynthesis and Sirtuin 3 (SIRT3) activity, thus fostering antioxidant defenses and ATP production. The functional role of SIRT3 in tubular recovery is highlighted by data that in SIRT3-deficient mice with AKI, UC-MSC treatment fails to induce renoprotection. These data document a previously unrecognized mechanism through which UC-MSCs facilitate renal repair, so as to induce global metabolic reprogramming of damaged tubular cells to sustain energy supply.

Mitochondria are dynamic organelles whose functions are tightly regulated at multiple levels to maintain proper cellular homeostasis. Mitochondrial Sirtuin 3 (SIRT3), which belongs to an evolutionary conserved family of NAD⁺-dependent deacetylases, is a key regulator of the mitochondrial respiratory chain, ATP production, and fatty acid β-oxidation, and it exerts an antioxidant activity. Changes in SIRT3 expression are critical in the pathophysiology of several diseases, such as metabolic syndrome, diabetes, cancer, and aging. In experimental acute kidney injury (AKI), impairment of renal function and development of tubular injury are associated with SIRT3 reduction and mitochondrial dysfunction in proximal tubuli. SIRT3-deficient mice are more susceptible to AKI and die. Pharmacological manipulations able to increase SIRT3 preserve mitochondrial integrity, markedly limit renal injury, and accelerate functional recovery. This review highlights all the selective rescue mechanisms that point to the key role of SIRT3 as a new therapeutic target for curing renal diseases.

Shiga toxin (Stx)-producing Escherichia coli is the offending agent of postdiarrhea-associated hemolytic uremic syndrome (HUS), a disorder of glomerular ischemic damage and widespread microvascular thrombosis. We previously documented that Stx induces glomerular complement activation, generating C3a responsible for microvascular thrombosis in experimental HUS. Here, we show that the presence of C3 deposits on podocytes is associated with podocyte damage and loss in HUS mice generated by the coinjection of Stx2 and LPS. Because podocyte adhesion to the glomerular basement membrane is mediated by integrins, the relevance of integrin-linked kinase (ILK) signals in podocyte dysfunction was evaluated. Podocyte expression of ILK increased after the injection of Stx2/LPS and preceded the upregulation of Snail and downregulation of nephrin and a-actinin-4. Factor B deficiency or pretreatment with an inhibitory antibody to factor B protected mice against Stx2/LPS-induced podocyte dysregulation. Similarly, pretreatment with a C3a receptor antagonist limited podocyte loss and changes in ILK, Snail, and a-actinin-4 expression. In cultured podocytes, treatment with C3a reduced a-actinin-4 expression and promoted ILK-dependent nuclear expression of Snail and cell motility. These results suggest that Stx-induced activation of the alternative pathway of complement and generation of C3a promotes ILK signaling, leading to podocyte dysfunction and loss in Stx-HUS.