The laboratory has developed experimental models of renal diseases, which accurately reproduce clinical and histopathological features of human nephropathies.
The aim is to investigate mediators and molecular mechanisms responsible for the progression to end-stage renal disease and to identify strategies able to slow down or even halt it.
The laboratory has expertise in pathology, immunopathology and molecular biology techniques to be applied to the study of kidney and other organs.
Experimental models of kidney disease
Currently, we are focusing our research on experimental models that replicate certain human kidney diseases, including: -rapidly progressive autoimmune glomerulonephritis, a serious form of kidney disease leading to terminal renal failure. To date, therapy is based on the use of immunosuppressive drugs with significant side effects and not always effective completions results. We identified the cellular populations involved in the formation of glomerular lesions, called "crescents", opening the possibility of new targeted therapies, reducing or eliminating the need for immunosuppressants. In our Laboratory studies are underway to evaluate the effectiveness of new molecules. - Focal segmentary glomerulosclerosis (FSGS), a rare but significant cause of terminal renal failure in children and adults. Current therapy does not guarantee lasting remission, highlighting the urgent need for new treatments. FSGS leads to renal fibrosis, characterized by excessive extracellular matrix deposition and complex intracellular signaling processes. Counteracting these pathways could be a potential therapeutic strategy for FSGS. - polycystic kidney disease, a genetic disease characterized by the formation of cysts in the kidneys and other organs, which cause progressive loss of kidney function. Currently therapy focuses on the signaling pathways involved in the formation of cysts. Fibrosis and inflammation are the main manifestations associated with the progression of the disease. We’re testing new molecules to limit these alterations.
New therapeutic approaches for diabetic nephropathy
We have a model of mice with type 2 diabetes and kidney disease that is a fundamental tool for identifying pathogenic mechanisms and new therapies for ND. Diabetic disease is associated with increased oxygen free radicals and reduced anti-oxidant capabilities, which contribute to its progression. Sirtuin 3 (SIRT3), a deacetylase prevalent in mitochondria, regulates the potential cellular reductive-oxide. Our research showed a decrease in SIRT3 during hyperglycemia, but the use of a specific activator was effective in reducing oxidative stress in kidney cells, thus improving kidney function. Given the emerging role of glomerular capillary endothelium in ND, we are investigating new targeted therapies to prevent alterations or promote regeneration. In mice with type 2 ND we observed a reduction in peritubular capillary density and detected abnormalities in endothelial glycocalice thanks to ultrastructural analysis. Treatment with an angiotensin-converting enzyme inhibitor (acea) safeguarded glycocalice and attenuated capillary abnormalities, indicating the importance of preserving these structures during disease development.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors in diabetic and non diabetic renal diseases
Type 2 sodium glucose transporter inhibitors (SGLT2) are approved drugs for the treatment of type 2 diabetes, which, in addition to reducing hyperglycemia, have protective effects on the kidney. We recently demonstrated the effectiveness of an SGLT2 inhibitor in a model of non-diabetic kidney disease characterized by proteinuria and damage to podocytes. In another study in BTBR ob/ob mice, which develop ND type 2, we demonstrated that treatment with an SGLT2 inhibitor limited the development of albuminuria, preserving the ultrastructure of the glomerular endothelium (completely subverted in these animals). During the study of the possible mechanisms by which the SGLT2 inhibitor was able to preserve the glomerular endothelium, we demonstrated that the drug reduced the increased expression of VEGF-A in the podocytes of diabetic mice, limiting at the endothelial level the altered expression of caveolin-1 and PV-1 proteins, for which VEGF-A represents a stimulus. These proteins are involved in the regulation of endothelial permeability and their normalization preserves the function of the glomerular endothelium and its permeability.
Strategies to inhibit complement activation
C3 glomerulopathy (C3G) is a rare disease caused by an abnormal activation of the complement system leading to chronic renal failure. The Laboratory has mice deficient for Factor H (a complement regulatory protein) that spontaneously develop C3G, with aberrant activation of the complement that leads to the consumption of circulating C3 and the accumulation of C3 deposits in the kidney. In haploinsufficient H-factor mice (Cfh+/-mice) we demonstrated that treatment with "small interfering" RNA (siRNA), which was able to selectively silence C3 expression in the liver, limited activation of the alternative complement pathway, reducing the fragmentation of circulating C3 and factor B. Treatment with C3 siRNA reduced glomerular deposits of C3 and slowed the formation of mesangial and subendotelial electron deposits. The results obtained indicate that selective C3 silencing in the liver by siRNA can be considered a relevant therapeutic strategy for treating patients with C3G associated with factor H haploinsufficiency. Uremic hemolytic syndrome (HUS) is a rare disease characterized by hemolytic anemia, thrombocytopenia and thrombosis, mainly at the renal level. The atypical form (aSEU) is of genetic origin and causes an uncontrolled activation of the complement system. We used mice with mutations in Factor H to understand its pathophysiology. The mutation worsened kidney failure and thrombophilia and increased complement activation and inflammation. Experimental treatment with a C5a receptor antagonist has been shown to improve renal function and reduce inflammation, suggesting a possible new therapeutic approach to treating this disease.
International Consensus on Cardiopulmonary Resuscitation.
