Genetics and cell biology

Cystic Kidney Disorders

Group leader

Alessandra Boletta

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 and ADPKD is a ciliopathy. The precise function of the two genes and proteins and the pathogenetic mechanism leading to cyst formation remain largely elusive.

Over the years this unit found that Polycystin-1 and 2 regulate the cellular cytoskeleton, cell migration and cell polarity in processes that are relevant for tissue morphogenesis in the developing kidney.Furthermore, the unit discovered that metabolic reprogramming is a key feature of PKD which includes the use of aerobic glycolysis, glutaminolysis, fatty acids biosynthesis and mitochondrial impairment. Several, but not all, of the metabolic derangements observed depend on the mTOR pathway. Finally, the lab is interested in studying if and how primary cilia, an important subcellular compartment where the polycystins localize, regulate any of the altered processes described above.

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Research activity

Key questions that we are trying to address are:

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? Are primary cilia involved?
Why despite the numerous similarities with cancer, PKD cysts do not transform into carcinomas?

In recent years the unit has generated mice lacking the Tsc1 gene in the kidney, showing that they undergo slowly progressive cyst formation caused by downregulation of Polycystin-1. Of interest, the cysts progressively transform into cystadenomas and carcinomas (RCC), a progression never observed in any of the PKD models. This group is focusing on studying the metabolic alterations downstream of the mTORC1 pathway that drive the transformation of renal epithelia into cystadenomas and carcinomas.

Finally, the group is interested in developing therapeutics based on the metabolic alterations observed in PKD and RCC.

Selected publications

Boletta A. Reversing polycystic kidney disease. Nat Genet. 2021, 53(12):1623-1624.

Nigro EA, Boletta A. Role of the polycystins as mechanosensors of extracellular stiffness. Am J Physiol Renal Physiol. 2021 May 1;320(5):F693-F705.

Cassina L, Boletta A. Metabolic reprogramming in polycystic kidney disease explained by super-enhancers and CDK7: new therapeutic targets? Nat Metab. 2020 Aug;2(8):659-660.

Cassina L, Chiaravalli M, Boletta A. Increased mitochondrial fragmentation in polycystic kidney disease acts as a modifier of disease progression. FASEB J. 2020 34(5):6493-6507.

Podrini C, Cassina L, Boletta A. Metabolic reprogramming and the role of mitochondria in polycystic kidney disease. Cell Signal. 2020 Mar;67:109495.

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

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.