The main aim is to study the renoprotective and regenerative capacity of therapies using adult or embryonic stem cells (induced pluripotent cells) of different origins, in models of acute and chronic kidney diseases.
We also identify the mechanisms of actions that regulate the interaction of different renal cellular populations with their progenitors during the progression of kidney diseases.
Another line of research focuses on the study of the embryonic kidney during different phases of development by using mice deficient for genes that influence nephrogenesis and that have an impact on their susceptibility to kidney diseases in adulthood.
As regards thromboticmicroangiopathies, our group investigates the mechanisms linked to theactivation of the complement system that favor thrombosis, with the aim of findinginnovative therapies. Moreover, the researchers carry out tests regarding the diagnosis and monitoring of standard therapyfor these pathologies.
Role of adult or embryonic stem cell (induced pluripotent)-based therapies in experimental models of kidney diseases
In order to identify the most promising stromal cell population for kidney repair and regeneration, we are studying the therapeutic effects of human mesenchymal stromal cells (MSCs) isolated from bone marrow, the umbilical cord or kidneys in models of chronic kidney disease. Results show that all three stromal cell populations, but particularly the MSCs obtained from umbilical cord, can preserve glomerular and tubular structures. In parallel, we are evaluating the therapeutic efficacy of renal precursors derived from induced pluripotent stem cells in experimental models of chronic kidney disease.
Complement proteins in diabetic nephropathy
Diabetic nephropathy is the most common cause of renal failure and is characterized by lesions affecting glomerular epithelial cells or podocytes, which lead to renal function impairment. New evidence suggests that activation of the complement system may play a crucial role in disease progression. Our studies have identified Complement (C) 3a, generated by the enzymatic cleavage of C3 during the complement activation cascade, as a key mediator of podocyte damage in a mouse model of type 2 diabetic nephropathy. Treatment with a C3a receptor antagonist limits the development of albuminuria in mice with diabetic nephropathy, reducing the glomerular damage. Ongoing studies will identify the intracellular mechanisms that are activated by the binding of C3a to its receptor, which underlie the development of renal lesions in diabetes.
Mitochondria and renal damage
Over the last few years, our group has been investigating the role that mitochondria play in the progression of acute and chronic kidney diseases. Mitochondria are highly dynamic organelles that adapt their shape in order to regulate energy production and other cellular processes, including cell survival. In an experimental model of acute kidney injury, we have shown that impaired function and structure in mitochondria are early pathologic hallmarks of acute renal damage and that their protection can be used to achieve tissue regeneration. More recently, we have also established that alterations to mitochondrial structural and functional integrity are a central pathogenic mechanism for the progression of chronic kidney diseases. The use of compounds that can preserve mitochondrial fitness could be a valuable pharmacological tool to slow or halt the progression of renal disorders.
Embryonic kidney development
Our research aims to identify the mechanisms involved in the development of the embryonic kidney which, if altered, can determine the onset of renal pathologies in post-natal life. Specifically, we are studying the role that the mitochondrial protein Sirtuin 3 plays in the kidney development. The results obtained in animals deficient for Sirtuin 3 demonstrated that this protein is fundamental for correct nephrogenesis and for having an adequate nephron number at birth. Ongoing studies aim to identify the mechanisms through which Sirtuin 3 regulates mitochondrial metabolism, influencing kidney development. These data are clinically important, considering that a low number of nephrons at birth constitutes a risk factor for the onset of kidney diseases in adulthood.
Study of the pathogenetic role of complement in thrombotic microangiopathies
We have developed an ex vivo test with human endothelial cells from the microcirculation to monitor, at the endothelial level, the activation of the complement induced by serum from patients with thrombotic microangiopathies, such as hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (PTT). This test allowed us to demonstrate that serum from patients that was collected during the acute phase, but not in remission, induced more extensive complement deposits than serum from healthy subjects on unstimulated cells. On stimulated cells, the serum from patients who were in remission also increased C3 and C5b-9 deposits. These data suggest that in HUS and PTT there is uncontrolled activation of the complement at the endothelial level that leads to thrombosis in the microcirculation. This test allows us to monitor disease activity and the efficacy of standard treatment. Furthermore, we used this test to evaluate activity at the endothelial level of potential new complement inhibitor drugs.
International Consensus on Cardiopulmonary Resuscitation.