Alessia Fornoni

Personal Information
Title Director
Expertise Nephropathy
Institution University of Miami - Medical Campus
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Data Summary
Grants/SubContracts 2
Progress Reports 1
Publications 13
Protocols 0
Committees 2

Role of Podocyte Lipids in the Prediction of Diabetic Nephropathy
Diabetic kidney disease (DKD) is responsible for nearly half of the incident end-stage kidney disease (ESKD) in the USA. Early clinical diagnosis of DKD is primarily based on measurement of urinary albumin-to-creatinine ratios (ACR), but significant DKD lesions can be present in the absence of elevated ACR. Several histological features are associated with progressive kidney disease and correlate with DKD lesions in both type 1 and type 2 diabetes (T1D and T2D); among them, podocyte foot process effacement and decreased podocyte number. Intracellular lipid accumulation is described in glomeruli of rodent models of DKD. Whether lipid accumulation in podocytes contributes to the progression of DKD, however, remains to be established. Our preliminary data demonstrate that normal cultured human podocytes exposed to the sera of patients with T1D and DKD accumulate total and esterified cholesterol whereas those exposed to sera from patients with T1D of similar duration and no DKD do not. Podocytes that accumulate lipid exhibit significant actin remodeling and increased apoptosis. This proposal will help us determine the role of intracellular lipid accumulation in the initiation and progression of DKD. We hypothesize that accumulation of intracellular lipid within podocytes precedes and predicts clinically apparent DKD and that a minimally invasive in vitro bioassay can be developed to predict DKD risk prior to increases in ACR in patients with T1D (University of Minnesota cohort) and T2D (Pima Indian cohort). We propose the following Specific Aims: 1. Develop a bioassay that predicts DKD using normal cultured human podocytes exposed to the sera of diabetic patients. 2. Develop a morphometric method to quantify lipid accumulation in podocytes. Assays developed with this application will then be utilized for subsequent larger interinstitutional and interdepartmental proposals to validate the association between lipid accumulation in podocytes and the development and progression of DKD in both T1D and T2D.
Clinical Development of Hydroxy-propyl beta cyclodextrin in Diabetic Kidney Disease
Diabetic kidney disease (DKD) is the most common cause of end-stage kidney disease in the US (1). Podocyte injury is an important feature of DKD in patients with T1D or T2D (2-6), and podocytopenia is an independent predictor of DKD progression. However, mechanisms of podocytopenia in DKD are poorly understood. In diabetes, cholesterol accumulation in adipocytes and hepatocytes contributes to actin cytoskeleton remodeling (7), insulin resistance (8) and cell death (9,10). Excessive cholesterol deposition has also been described in glomeruli of rodent models of T1D and T2D (11-13) and can result from impaired cholesterol efflux due to down-regulation of ATP-binding cassette transporter (ABCA1) expression (11,13). Under normal conditions, ABCA1 mediates the efflux of cholesterol and phospholipids to lipid-poor apolipoproteins (primarily apo-A1), which then form nascent high-density lipoproteins (HDL). Our preliminary data in glomerular transcripts from 70 patients with T2D and early DKD demonstrated down-regulation of ABCA1 when compared with living transplant donors. In further preliminary data, cholesterol accumulation and down-regulation of ABCA1 occurred in podocytes exposed to the sera of patients with DKD or in response to inflammatory stimuli related to DKD progression such as TNF-alpha and its soluble receptors TNFR1 and TNFR2. Therefore, interventions that increase ABC expression (such as liver X receptor agonist) may be beneficial in DKD but are limited by the high incidence of adverse events (14) and by their intrinsic lipogenic effects (15). One potential alternative to this limitation is to utilize drugs that sequester cholesterol, such as cyclodextrins (16,17). Cyclodextrins are cyclic oligosaccharides utilized in the food, drug delivery and chemical industries. Hydroxy-propyl-beta cyclodextrin (CD) is also being investigated for the treatment of Niemann-Pick disease type C1, a genetic disorder characterized by lysosomal accumulation of cholesterol leading to multiple organ dysfunction (18). Our preliminary data suggest that high dose CD may protect podocyte function in DKD by reducing their cholesterol content, but whether this is true for lower doses that are translatable to humans remains to be established. Based on these observations, we hypothesize that low dose CD protects podocytes in DKD. To determine the effects of low dose subcutaneous CD on cholesterol accumulation in podocytes, and its impact on podocyte injury, we will use animal models of T2D and human podocytes cultured in the presence of the sera of patients with T2D. We will also determine if low dose CD administered orally has a similar effect on macroalbuminuria of CD administered subcutaneously since oral administration of CD at 40 mg/kg/day is well tolerated and is as effective as subcutaneous CD in reducing microalbuminuria in BTBR ob/ob mice. Our proposal for the Preclinical Testing Program has high opportunity to translate into successful drug development for the care of patients with DKD. This will be highly feasible, as we have already reported that high dose CD protects from DKD, we have obtained from Johnson & Johnson the CD drug master file in preparation of our meeting with the FDA for the utilization of CD for DKD, and CD is currently used by NIH in a Phase 1 trial for the treatment of Niemann-Pick Disease Type C1.

Progress Reports

Annual Reports
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 PublicationAltmetricsSubmitted ByPubMed IDStatus

Year: 2019; Items: 2

SMPDL3b modulates insulin receptor signaling in diabetic kidney disease.
Mitrofanova A, Mallela SK, Ducasa GM, Yoo TH, Rosenfeld-Gur E, Zelnik ID, Molina J, Varona Santos J, Ge M, Sloan A, Kim JJ, Pedigo C, Bryn J, Volosenco I, Faul C, Zeidan YH, Garcia Hernandez C, Mendez AJ, Leibiger I, Burke GW, Futerman AH, Barisoni L, Ishimoto Y, Inagi R, Merscher S, Fornoni A
Nature communications, 2019 (10), 2692
Lipid Mediators of Insulin Signaling in Diabetic Kidney Disease.
Mitrofanova A, Sosa MA, Fornoni A
American journal of physiology. Renal physiology, 2019

Year: 2016; Items: 3

CTLA4-Ig in B7-1-positive diabetic and non-diabetic kidney disease.
Bassi R, Fornoni A, Doria A, Fiorina P
Diabetologia, 2016 (59), 21 - 9
Drug discovery in focal and segmental glomerulosclerosis.
Pullen N, Fornoni A
Kidney international, 2016 (89), 1211 - 20
Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injury.
Pedigo CE, Ducasa GM, Leclercq F, Sloan A, Mitrofanova A, Hashmi T, Molina-David J, Ge M, Lassenius MI, Forsblom C, Lehto M, Groop PH, Kretzler M, Eddy S, Martini S, Reich H, Wahl P, Ghiggeri G, Faul C, Burke GW, Kretz O, Huber TB, Mendez AJ, Merscher S, Fornoni A
The Journal of clinical investigation, 2016 (126), 3336 - 50

Year: 2015; Items: 3

Sphingomyelinase-like phosphodiesterase 3b expression levels determine podocyte injury phenotypes in glomerular disease.
Yoo TH, Pedigo CE, Guzman J, Correa-Medina M, Wei C, Villarreal R, Mitrofanova A, Leclercq F, Faul C, Li J, Kretzler M, Nelson RG, Lehto M, Forsblom C, Groop PH, Reiser J, Burke GW, Fornoni A, Merscher S
Journal of the American Society of Nephrology : JASN, 2015 (26), 133 - 47
Insulin signaling: implications for podocyte biology in diabetic kidney disease.
Coward R, Fornoni A
Current opinion in nephrology and hypertension, 2015 (24), 104 - 110
Nephrin Contributes to Insulin Secretion and Affects Mammalian Target of Rapamycin Signaling Independently of Insulin Receptor.
Villarreal R, Mitrofanova A, Maiguel D, Morales X, Jeon J, Grahammer F, Leibiger IB, Guzman J, Fachado A, Yoo TH, Busher Katin A, Gellermann J, Merscher S, Burke GW, Berggren PO, Oh J, Huber TB, Fornoni A
Journal of the American Society of Nephrology : JASN, 2015

Year: 2014; Items: 1

Podocyte-specific GLUT4-deficient mice have fewer and larger podocytes and are protected from diabetic nephropathy.
Guzman J, Jauregui AN, Merscher-Gomez S, Maiguel D, Muresan C, Mitrofanova A, Diez-Sampedro A, Szust J, Yoo TH, Villarreal R, Pedigo C, Molano RD, Johnson K, Kahn B, Hartleben B, Huber TB, Saha J, Burke GW, Abel ED, Brosius FC, Fornoni A
Diabetes, 2014 (63), 701 - 714

Year: 2013; Items: 1

Cyclodextrin protects podocytes in diabetic kidney disease.
Merscher-Gomez S, Guzman J, Pedigo CE, Lehto M, Aguillon-Prada R, Mendez A, Lassenius MI, Forsblom C, Yoo T, Villarreal R, Maiguel D, Johnson K, Goldberg R, Nair V, Randolph A, Kretzler M, Nelson RG, Burke GW, Groop PH, Fornoni A
Diabetes, 2013 (62), 3817 - 3827

Year: 2012; Items: 1

Beneficial effects of ischemic preconditioning on pancreas cold preservation.
Hogan AR, Doni M, Molano RD, Ribeiro MM, Szeto A, Cobianchi L, Zahr-Akrawi E, Molina J, Fornoni A, Mendez AJ, Ricordi C, Pastori RL, Pileggi A
Cell transplantation, 2012 (21), 1349 - 1360
Submitted Externally

Year: 2011; Items: 2

Proteinuria in diabetes: an endocrine disease?
Lenz O, Fornoni A
Current diabetes reviews, 2011 (7), 1 - 2
Podocytopathy in diabetes: a metabolic and endocrine disorder.
Diez-Sampedro A, Lenz O, Fornoni A
American journal of kidney diseases : the official journal of the National Kidney Foundation, 2011 (58), 637 - 646
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