Sassi, A. | Search bioRxiv

bioRxiv2021

A new variant of ASIC2 mediates sodium retention in nephrotic syndrome

Idiopathic nephrotic syndrome (INS) is characterized by proteinuria and renal Na retention leading to oedema. This Na retention is usually attributed to epithelial sodium channel (ENaC) activation following plasma aldosterone increase. However, most nephrotic patients show normal aldosterone levels. Using a corticosteroid-clamped rat model of INS (CC-PAN), we showed that the observed electrogenic and amiloride-sensitive Na retention could not be attributed to ENaC. We, then, identified a truncated variant of acid sensing ion channel 2b (ASIC2b) that induced sustained acid-stimulated sodium currents when co-expressed with ASIC2a. Interestingly, CC-PAN nephrotic ASIC2b-null rats did not develop sodium retention. We finally showed that expression of the truncated ASIC2b in kidney was dependent on the presence of albumin in the tubule lumen and activation of ERK in renal cells. Finally, the presence of ASIC2 mRNA was also detected in kidney biopsies from patients with INS but in any of the patients with other renal diseases. We have, therefore, identified a novel variant of ASIC2b responsible for the renal Na retention in the pathological context of INS.

pathology↗

bioRxiv2017

Molecular chaperones inject energy from ATP hydrolysis into the non-equilibrium stabilisation of native proteins

Protein homeostasis, namely the ensemble of cellular mechanisms collectively controlling the activity, stability and conformational states of proteins, depends on energy-consuming processes. De novo protein synthesis requires ATP hydrolysis for peptide bond formation. Controlled degradation by the chaperone-gated proteases requires ATP hydrolysis to unfold target proteins and render their peptide bonds accessible to hydrolysis. During and following translation, different classes of molecular chaperones require ATP hydrolysis to control the conformational state of proteins, favor their folding into their active conformation and avoid, under stress, their conversion into potentially harmful aggregates. Furthermore, specific ATP-fueled unfolding chaperones can dynamically revert aggregation itself. We used here various biochemical assays and physical modeling to show that both bacterial chaperones GroEL (HSP60) and DnaK (HSP70) can use the energy liberated by ATP hydrolysis to maintain proteins in their active state even under conditions that do not favor, thermodynamically, the native state. The energy from ATP hydrolysis is thus injected by the chaperones in the system and converted into an enhanced, non-equilibrium steady-state stabilization of the native state of their substrates. Upon ATP consumption, the chaperone substrates spontaneously revert to their equilibrium non-native state.

biochemistry↗