In the field of acute and chronic kidney diseases, the laboratory’s focus is on identifying new therapeutic strategies to restore the structure and function of damaged organs, exploring new approaches based on regenerative medicine using stem cells and their biological products. With the ultimate aim of identifying new treatments for patients, the laboratory also studies the pathogenetic mechanisms that underlie the onset and progression of different types of kidney diseases. Specifically, we are studying the involvement of the complement system in the pathogenesis of diabetic nephropathy and rare renal diseases with thrombotic manifestations, such as haemolytic uremic syndrome and thrombotic thrombocytopenic purpura.
Following the recent COVID-19 pandemic, we are studying the mechanisms leading to pulmonary endothelial cell damage in the thromboembolic processes observed in COVID-19 patients.
The embryonic origin of kidney diseases in adults
A baby born prematurely and/or with low birth weight has a higher risk of developing hypertension, cardiovascular disease and kidney damage as an adult. The mechanisms that link embryonic development under disadvantageous conditions and the onset of pathologies in postnatal life remain unclear. However, it is known that low birth weight is associated with fewer nephrons, the filtering units of the kidney. Our research aims to identify the mechanisms involved in the development of the kidney which, if altered, can increase the susceptibility to develop kidney diseases in postnatal life. In this context, we are studying the role that the mitochondrial protein SIRT3 plays in nephrogenesis and evaluating the possibility that it may be a valid target for normalising nephron numbers.
Renal regenerative medicine
Cell therapy is the new frontier of regenerative medicine. Our laboratory, which has been studying stem cells/precursors of different origins for the treatment of acute and chronic kidney diseases for some time, has recently demonstrated the great therapeutic efficacy of stromal mesenchymal cells isolated from umbilical cord blood in the treatment of kidney diseases. The regenerative action passes through the secretion of biologically active substances and extracellular vesicles which promote regeneration also through the preservation of mitochondria, important organelles controlling the energy metabolism and the antioxidant activities of the cells. This discovery changes our perspective on cell therapies: cells can in fact be vehicles for pro-regenerative substances to the site of damage. Our studies therefore focus on identifying these cellular products and on developing strategies, which include cellular engineering approaches, to increase their therapeutic efficacy.
Complement proteins in diabetic nephropathy
Our laboratory has contributed to understanding the mechanisms underlying the development of diabetic nephropathy. For the first time, we have shown that the activation of the complement system, which is fundamental for our immune system, causes the generation of the active C3a protein that is an important mediator of renal damage in the glomerulus as it causes podocyte dysfunction and loss. In experimental models of diabetic nephropathy, we have demonstrated that treatment with a C3a receptor antagonist improves renal function and preserves the glomerular structure protecting the integrity of the mitochondrial network in podocytes. These data are an important starting point for developing effective innovative therapies for treating diabetic nephropathy.
Complement proteins in thrombotic microangiopathies
The aim of this line of research is to understand whether complement proteins, which are fundamental elements of our immune system, can be mediators of damage and possible therapeutic targets in thrombotic microangiopathies, such as haemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (PTT). We have developed an ex vivo assays that allowed us to discover that in HUS and PTT there is uncontrolled activation of the complement at the endothelial level, which leads to the formation of thrombi in the microcirculation. This assay allows us to monitor both the activity of the disease, differentiating between the acute phase and remission, and to test the effectiveness of the drug treatment patients receive. Furthermore, with this test we are evaluating the activity of new drugs that inhibit complement at the endothelial level.
Cellular mechanisms underlying endothelial damage and thrombosis in severe COVID-19
In response to the recent COVID-19 pandemic, the laboratory investigated the cellular mechanisms activated by SARS-CoV-2 in vitro that leads to the endothelial damage that underlies the thrombotic phenomena that frequently occur in patients with severe forms of COVID-19. Specifically, the laboratory has shown that exposure of microvascular endothelial cells to SARS-CoV-2 spike 1 (S1) protein induced the expression of the adhesive molecule ICAM-1 and von Willebrand Factor, which associated with inflammatory cell adhesion and thrombus formation, respectively. In this context, complement activation plays a key role in exacerbating S1-induced endothelial damage and inhibitors of the complement system are effective in limiting S1-induced endothelial damage. The laboratory is also developing an in vivo model with human ACE2 transgenic mice to evaluate how S1 injection can induce acute lung injury characterized by endothelial damage and complement activation.
Long-term humoral and cellular response in subjects exposed to SARS-CoV-2 infection or who got vaccinated
As part of the scientific response to the COVID-19 pandemic, the laboratory investigated the spread of SARS-CoV-2 through the use of serological tests and antigenic swabs to identify the presence of specific antibodies to different viral various proteins or the genetic material of the virus in the population of the province of Bergamo, one of the most affected during the first pandemic wave of March 2020. More recently, the laboratory is monitoring how the immune protection guaranteed by vaccination evolves over time both in terms of humoral immunity, neutralizing antibodies with the ability to block viral infection in cultured cells, as well as the cellular immunity provided by memory T and B cells.
International Consensus on Cardiopulmonary Resuscitation.