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 otherorgans.
Development of experimental models
The laboratory has set up a model of rapidly progressive autoimmune glomerulonephritis, one of the most serious renal diseases that causes terminal organ failure. The current therapy is based on immunosuppressive drugs, which, in addition to causing important side effects, often result not completely effective. We have characterized the glomerular cell populations involved in the formation of “crescents”, the typical lesions of this pathology, that may be targets of new therapies and may allow sparing immunosuppressants. Studies are ongoing to assess the efficacy of new molecules.
New therapeutic approaches for diabetic nephropathy
We have available a mouse model of type 2 diabetic nephropaty (DN) which is a suitable tool to identify pathogenetic mechanisms/signaling as potential targets for therapy in DN. The increased production of reactive oxygen species (ROS) and insufficient antioxidant capacity are main mediators of kidney damage and progressive disease induced by diabetes. Sirtuin 3 (SIRT3) is the main mitochondrial deacetylase that critically regulates ROS production and detoxification. We have demonstrated that renal expression of SIRT3 is reduced by hyperglycemia in diabetic mice and that treatment with a specific SIRT3 activator is able to reduce oxidative stress in glomerular and tubular epithelial cells, resulting in a reduction of albuminuria and amelioration of renal damage.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors in diabetic and non diabetic renal diseases
SGLT2 inhibitors are drugs approved for the treatment of type 2 diabetes that beyond blood glucose lowering effects, display renoprotective effects in diabetic kidney disease. Recently, the laboratory has demonstrated the efficacy of these drugs even in a mouse model of non-diabetic nephropathy induced by protein overload and characterized by proteinuria and podocyte damage. In another study, in BTBR ob/ob mice that develop a type 2 diabetic nephropathy, we have showed that treatment with a SGLT2 inhibitor limited albuminuria by ameliorating the subverted microvascular endothelial ultrastructure. To elucidate the possible mechanisms underlying the ability of SGLT2 inhibitor to preserve glomerular endothelium, we showed that the drug normalized podocyte VEGF-A overexpression, limiting its paracrine signaling on endothelial proteins caveolin-1 and PV-1, that are involved in the regulation of glomerular endothelial function and permeability.
Strategies to inhibit complement activation
C3 glomerulopathy (C3G) is a rare renal disease caused by dysregulation of the alternative pathway of complement system that can lead to kidney failure. No disease-specific treatments are currently available for C3G. The laboratory has available deficient mice for factor H, a regulatory protein of the complement system, which spontaneously develop C3G exhibiting uncontrolled activation of complement, decreased levels of circulating C3 and accumulation of C3 deposits in the kidney. In the C3G model of mice with heterozygous deficiency of factor H (Cfh+/- mice) we have demonstrated that treatment with a small interfering RNA (siRNA) able to specifically inhibit the production of C3 by the liver, limited alternative pathway activation, reducing circulating C3 and factor B fragmentation. C3 siRNA decreased glomerular C3d deposits and slowed the formation of mesangial and sub-endothelial electron deposits. These data indicate that RNA interference-mediated C3 silencingin the liver may be an important therapeutic strategy for treating patients with C3G associated with the haploinsufficiency of factor H.
International Consensus on Cardiopulmonary Resuscitation.
