Molecular basis of cystic kidney disorders
The unit is interested in understanding the morphogenetic mechanisms driving establishment and maintenance of renal tubular diameter in physiological conditions and that are deranged in pathologies such as cystic kidney disorders. This group uses as a prototype disease Polycystic Kidney Disease (PKD), a genetic disorder, due to mutations in two genes: PKD1 and PKD2, encoding for two membrane proteins Polycystin-1 and 2, respectively. The two proteins localize in cilia, their precise function is unclear.
Over the years this unit found that Polycystin-1 and 2 regulate the cellular cytoskeleton and cell migration as well as tissue morphogenesis in the developing kidney. Furthermore, they discovered that metabolic reprogramming is a key feature of PKD which includes the use of aerobic glycolysis, glutaminolysis and mitochondrial impairment. Several of these derangements depend on the mTOR pathway.
- What is the normal function of the Polycystins? And their role in epithelial morphogenesis during renal development?
- Is the function of the polycystins exclusively due to their activity in cilia, or there are additional functional roles for these proteins?
- What is the origin of the metabolic derangement and mitochondrial alterations observed in PKD animal models?
- Why despite the numerous similarities with cancer, PKD cysts do not transform into carcinomas?
Nigro EA, Distefano G, Chiaravalli M, Matafora V, Castelli M, Pesenti Gritti A, Bachi A, Boletta A. Polycystin-1 Regulates Actomyosin Contraction and the Cellular Response to Extracellular Stiffness. Sci Rep. 2019 Nov 12;9(1):16640.
Podrini C, Rowe I, Pagliarini R, Costa ASH, Chiaravalli M, Di Meo I, Kim H, Distefano G, Tiranti V, Qian F, di Bernardo D, Frezza C, Boletta A. Dissection of metabolic reprogramming in polycystic kidney disease reveals coordinated rewiring of bioenergetic pathways. Commun Biol. 2018 Nov 16;1:194.
Padovano V, Podrini C, Boletta A, Caplan MJ. Metabolism and mitochondria in polycystic kidney disease research and therapy. Nat Rev Nephrol. 2018 Nov;14(11):678-687. Review.
Drusian L, Nigro EA, Mannella V, Pagliarini R, Pema M, Costa ASH, Benigni F, Larcher A, Chiaravalli M, Gaude E, Montorsi F, Capitanio U, Musco G, Frezza C, Boletta A. mTORC1 Upregulation Leads to Accumulation of the Oncometabolite Fumarate in a Mouse Model of Renal Cell Carcinoma.Cell Rep. 2018 Jul 31;24(5):1093-1104.e6.
Chiaravalli M, Rowe I, Mannella V, Quilici G, Canu T, Bianchi V, Gurgone A, Antunes S, D’Adamo P, Esposito A, Musco G and Boletta A. 2-Deoxy-D- Glucose Effectively Ameliorates Polycystic Kidney Disease Progression, J. Am Soc. Neph. 2016 Jul;27(7):1958-69.
Pema M, Drusian L, Chiaravalli M, Castelli M, Yao Q, Ricciardi S, Somlo S, Qian F, Biffo S, Boletta A. mTORC1-mediated inhibition of polycystin-1 expression drives renal cyst formation in tuberous sclerosis complex. Nat Commun. 2016 Mar 2;7:10786
Nigro EA, Castelli M, Boletta A. Role of the Polycystins in Cell Migration, Polarity, and Tissue Morphogenesis. Cells. 2015 Oct 30;4(4):687-705.
Rowe I, Boletta A. Defective metabolism in polycystic kidney disease: potential for therapy and open questions. Nephrol Dial Transplant. 2014 Aug;29(8):1480-6.
Castelli M, Boca M, Chiaravalli M, Ramalingam H, Rowe I, Distefano G, Carroll T, Boletta A. Polycystin-1 Binds Par3/aPKC and Controls Polarized Cell Migration and Renal Tubular Morphogenesis. Nature Communications, 2013 Oct 24;4:2658.
Rowe I, Chiaravalli M, Mannella V, Ulisse V, Mari S, Pema M, Song X, Quilici G, Xueng H, Qian F, Pei Y, Musco G, Boletta A. Defective Glucose Metabolism in Polycystic Kidney Disease Identifies a Novel. Nat Med 2013 Apr;19(4):488-93.
Maria Elena Steidl