Vivette D D'Agati, MD

My translational research has focused primarily on FSGS, including characterization of the histologic variants, how they differ in clinical presentation and treatment response, and how they reflect different pathogenesis. I organized the first consensus classification of FSGS morphologic subtypes, often referred to as the “Columbia Classification”. As the lead pathologist in the NIH-sponsored FSGS-CT, I was able to confirm in an independent cohort of steroid-resistant children and young adults my earlier observations in Columbia cohorts that tip variant has the best outcome and collapsing variant the worst outcome in primary FSGS. Taken together, my work has contributed to the current view that FSGS is not a single disease, but a group of clinical-pathologic syndromes, and validates the clinical importance of identifying distinct FSGS disease subsets.

A major focus of my basic research is to explore how podocytes become dysregulated, lose maturity markers and eventually fail, leading to podocyte depletion as central mediator of FSGS. Using transcriptional profiling of microdissected glomeruli in human renal biopsies, we demonstrated podocyte dedifferentiation and expansion of stem cell and parietal cell compartments in variants of FSGS, but not minimal change disease. One of the most widely studied animal models of FSGS is adriamycin nephropathy, which is highly strain-dependent. Our group discovered a mutation in Prkdc, a member of the DNA break repair machinery, as the basis for genetic susceptibility to adriamycin nephropathy in Balb/c mice. This observation demonstrates the importance of protective mechanisms against genotoxic stress in podocytes, which lack the ability to repair by cell division. In an animal model of collapsing FSGS, we helped demonstrate the roles of telomerase and Wnt signaling in podocyte cell cycle dysregulation. Because podocytes are long-lived cells, they are particularly vulnerable to mitochondrial injury via oxidative stress. Studies of mitochondrial dysfunction in FSGS identified the role of endothelial-podocyte cross-talk, whereby podocyte release of endothelin-1 promotes endothelial oxidative stress and podocyte apoptosis through activation of TGFβ signaling.

My early clinical-pathologic descriptions and translational studies showing podocyte dysregulation in HIVAN led to a productive 20-year collaboration as Core Pathologist in the NIH-sponsored PPG studying HIVAN pathogenesis. Our group demonstrated the ability of HIV virus to directly infect renal epithelial cells, including podocytes, parietal cells and tubular cells, using in situ DNA PCR (performed in my laboratory) and in situ RNA hybridization (performed in Dr. Paul Klotman’s laboratory). Using laser capture microdissection of renal tubules coupled with HIV quasispecies analysis we demonstrated the ability of HIV virus to replicate and evolve in kidney epithelia as a separate compartment from peripheral blood. Our group went on to show how nef and vpr expression by renal epithelia causes the pathologic features of HIVAN by dysregulation of host genes governing cell cycle and differentiation. GWAS studies among inbred mouse strains using a murine model of HIVAN mapped susceptibility to the Ssbp2 locus. Ssbp2 is highly expressed in podocytes and encodes a transcriptional cofactor that interacts with LDB1 and LMX1B.