Renal proximal tubules are sensitive to metabolic acidosis

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Item Type:	Preprint
Title:	Renal proximal tubules are sensitive to metabolic acidosis
Creators Name:	Hennings, J.C., Murthy, K.S., Picard, N., Cabrita, I., Böhm, D., Krause, M.E., Shah, V., Baraka-Vidot, J., Khundadze, M., Stauber, T., Böckenhauer, D., Jentsch, T.J., Bachmann, S., Schermer, B., Eladari, D., Chambrey, R. and Hübner, C.A.
Abstract:	Patients suffering from distal renal tubular acidosis (dRTA) are sometimes diagnosed with proximal tubule dysfunction with leaks of phosphate, uric acid, amino acids, and low-molecular-weight proteins, also known as Fanconi-like syndrome. The underlying molecular basis is largely elusive. We previously reported on Atp6v0a4 knockout (KO) mice, which exhibit severe metabolic acidosis in combination with proximal tubule dysfunction as evidenced by phosphaturia and proteinuria. Here, we show that Rab7, a key regulator of endo-lysosomal trafficking and lysosomal biogenesis, is strongly diminished in proximal tubules of Atp6v0a4 KO mice, while the number of abnormal Ist1-labelled Lamp1-positive vesicles is increased. This is accompanied by the accumulation of autophagosomes, autolysosomes and autophagic substrates. Importantly, correction of metabolic acidosis with bicarbonate therapy resolves proximal tubule dysfunction and trafficking defects in Atp6v0a4 KO mice. Acid-challenged wildtype mice also show trafficking defects with Rab7-downregulation and an increase in Ist1-labeled Lamp1-positive vesicles and develop proximal tubule damage in the long-term. Similar acidosis-induced alterations also occur in human kidney organoids. Altogether, our data provide insights, why patients suffering from severe dRTA may develop a Fanconi-like syndrome, which may contribute to the progression of chronic kidney failure.
Keywords:	Fanconi Syndrome, Renal Tubular Acidosis, Chronic Kidney Disease, Animal Model, Animals, Mice
Source:	bioRxiv
Publisher:	Cold Spring Harbor Laboratory Press
Article Number:	10.1101/2024.08.19.608649
Date:	19 August 2024
Official Publication:	https://doi.org/10.1101/2024.08.19.608649

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