Post-translational modifications by SIRT3 de-2-hydroxyisobutyrylase activity regulate glycolysis and enable nephrogenesis

Luca Perico,Giuseppe Remuzzi,Fabio Sangalli,Ariela Benigni,Anna Pezzotta,Piera Trionfini,Sara Buttò,Barbara Imberti,Marina Morigi,Sara Conti,Carlamaria Zoja,Cristina Zanchi,Christodoulos Xinaris,Daniela Corna,Valerio Brizi,Susanna Tomasoni

doi:10.1038/s41598-021-03039-8

Luca Perico, Giuseppe Remuzzi + Show 14 more

Open Access

https://doi.org/10.1038/s41598-021-03039-8

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Abstract

Abnormal kidney development leads to lower nephron number, predisposing to renal diseases in adulthood. In embryonic kidneys, nephron endowment is dictated by the availability of nephron progenitors, whose self-renewal and differentiation require a relatively repressed chromatin state. More recently, NAD+-dependent deacetylase sirtuins (SIRTs) have emerged as possible regulators that link epigenetic processes to the metabolism. Here, we discovered a novel role for the NAD+-dependent deacylase SIRT3 in kidney development. In the embryonic kidney, SIRT3 was highly expressed only as a short isoform, with nuclear and extra-nuclear localisation. The nuclear SIRT3 did not act as deacetylase but exerted de-2-hydroxyisobutyrylase activity on lysine residues of histone proteins. Extra-nuclear SIRT3 regulated lysine 2-hydroxyisobutyrylation (Khib) levels of phosphofructokinase (PFK) and Sirt3 deficiency increased PFK Khib levels, inducing a glycolysis boost. This altered Khib landscape in Sirt3−/− metanephroi was associated with decreased nephron progenitors, impaired nephrogenesis and a reduced number of nephrons. These data describe an unprecedented role of SIRT3 in controlling early renal development through the regulation of epigenetics and metabolic processes.

Highlights

Abnormal kidney development leads to lower nephron number, predisposing to renal diseases in adulthood
To further assess what effect Sirt[3] deficiency has on renal cell precursor behaviour and activity, we studied the duration of nephrogenesis, which normally ceases by postnatal day 3 (P3) in mice[52,53], by analysing the presence of SIX2-positive cells in the kidneys on P3 and P4
To understand whether the altered renal progenitor cell behaviour induced by a Sirt[3] deficiency could result in impaired nephrogenesis and nephron number, we studied the morphogenesis of the ureteric bud (UB) on E12.5, using calbindin D28k staining

Summary

Introduction

Abnormal kidney development leads to lower nephron number, predisposing to renal diseases in adulthood. Extra-nuclear SIRT3 regulated lysine 2-hydroxyisobutyrylation (Khib) levels of phosphofructokinase (PFK) and Sirt[3] deficiency increased PFK Khib levels, inducing a glycolysis boost This altered Khib landscape in Sirt3−/− metanephroi was associated with decreased nephron progenitors, impaired nephrogenesis and a reduced number of nephrons. These data describe an unprecedented role of SIRT3 in controlling early renal development through the regulation of epigenetics and metabolic processes. Histone acetylation has been reported to regulate renal progenitor cell self-renewal and differentiation as the simultaneous deletion of both histone deacetylase 1 (Hdac1) and Hdac[2] in renal progenitor cells led to the arrest of nephrogenesis at the renal vesicle stage, renal hypodysplasia, and lethality shortly after birth[14] All these studies have shown that progenitor cell maintenance and proper differentiation require a relatively. Due to their predominant nuclear localization, SIRT1, SIRT6, and SIRT7 have been found to play critical roles in epigenetics across different t issues[15,16,17]

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