# Renal Intercalated Cells: Alien Cells Inside Us?

## TL;DR

This paper explores the unique biology of kidney intercalated cells and suggests they may have ancient evolutionary origins similar to simpler organisms.

## Contribution

The paper proposes a novel evolutionary origin for renal intercalated cells, linking them to ancient amoeboid cells and suggesting conserved biological functions.

## Key findings

- Intercalated cells use H+-ATPase, a mechanism found in simpler organisms, to energize themselves.
- These cells contribute to kidney defense and regeneration, similar to embryonic and cancer cells.
- The paper predicts that sponge amoebocytes and related cells share similar properties and evolutionary traits.

## Abstract

Intercalated cells are specialized kidney cells responsible for excreting acid produced daily by our bodies. These cells utilize H+-ATPase, a proton pump, to carry out this function. This pump energizes the cells, creating an internal environment distinct from the external world. However, most animal cells depend on a different mechanism—the sodium–potassium pump—to achieve this function. Cells energized by H+-ATPase are commonly observed in simpler organisms, including certain animals and unicellular protozoa. These cells play a crucial role in specific functions such as cell invasiveness, immune response, and stem cell behavior, distinguishing them from more typical cells that rely on the sodium–potassium pump. By reviewing the biological literature and confirming the presence of H+-ATPase-harboring cells across multiple species, we propose that these cells can be traced back through evolutionary history. The coexistence of two distinct cell types within the same organ presents an evolutionary advantage, as it allows the organ to maintain normal function while a subset of cells focuses on defense and regeneration when necessary. Remarkably, the ability to develop and maintain two distinct cellular frames has been conserved throughout evolution, from the simplest organisms to mammals, highlighting its fundamental biological significance.

Mammalian renal intercalated cells are known for their role in acid secretion and maintaining acid–base balance. Herein, we discuss the theoretical reasons behind their development based on published data, focusing on the unique characteristics of renal intercalated cell biology that distinguish them from other mammalian cell types, while simultaneously attempting to explain the persistence of cells similar to intercalated cells throughout evolution. In addition, we traced these characteristics phylogenetically back to the simplest organisms. Intercalated cells have several functions and attributes. First, they contribute to kidney defense mechanisms in response to both infectious and non-infectious kidney damage. Second, intercalated cells are energized by V-ATPases in a manner similar to that of protozoa. Third, they possess T-antigens, which are commonly found in embryonic and cancer cells and which confer invasive abilities to these cells. Fourth, their plasticity enables the regeneration of other epithelial cells. These observations indicate that the origins of renal intercalated cells may be traceable back to amoeboid cells that originated from an evolutionary lineage including protists, or even to the last eukaryote common ancestor. The theoretical framework presented herein supports two predictions: first, that sponge amoebocytes possess membrane V-ATPase and are sensitive to bafilomycin, but not to ouabain; and second, that sponge amoebocytes—along with cells from diploblasts (such as Xenacoelomorpha), cnidarians, worms, fish and mollusk ionocytes, and the entire cell lineage containing V-ATPase, carbonic anhydrase, and anion exchangers (HCO3−/Cl−)—have innate immunity, cellular dedifferentiation, and regeneration capabilities.