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Abstract
BackgroundCaveolae are membrane invaginations measuring 50–100 nm. These organelles, composed of caveolin and cavin proteins, are important for cellular signaling and survival. Caveolae play incompletely defined roles in human kidneys. Induction of caveolin-1/CAV1 in diseased tubules has been described previously, but the responsible mechanism remains to be defined.MethodsHealthy and atrophying human kidneys were stained for caveolar proteins, (caveolin 1–3 and cavin 1–4) and examined by electron microscopy. Induction of caveolar proteins was studied in isolated proximal tubules and primary renal epithelial cells. These cells were challenged with hypoxia or H2O2. Primary tubular cells were also subjected to viral overexpression of megakaryoblastic leukemia 1 (MKL1) and MKL1 inhibition by the MKL1 inhibitor CCG-1423. Putative coregulators of MKL1 activity were investigated by Western blotting for suppressor of cancer cell invasion (SCAI) and filamin A (FLNA). Finally, correlative bioinformatic studies of mRNA expression of caveolar proteins and MKL1 were performed.ResultsIn healthy kidneys, caveolar proteins were expressed by the parietal epithelial cells (PECs) of Bowman’s capsule, endothelial cells and vascular smooth muscle. Electron microscopy confirmed caveolae in the PECs. No expression was seen in proximal tubules. In contrast, caveolar proteins were expressed in proximal tubules undergoing atrophy. Caveolar proteins were also induced in cultures of primary epithelial tubular cells. Expression was not enhanced by hypoxia or free radical stress (H2O2), but proved sensitive to inhibition of MKL1. Viral overexpression of MKL1 induced caveolin-1/CAV1, caveolin-2/CAV2 and SDPR/CAVIN2. In kidney tissue, the mRNA level of MKL1 correlated with the mRNA levels for caveolin-1/CAV1, caveolin-2/CAV2 and the archetypal MKL1 target tenascin C (TNC), as did the MKL1 coactivator FLNA. Costaining for TNC as readout for MKL1 activity demonstrated overlap with caveolin-1/CAV1 expression in PECs as well as in atrophic segments of proximal tubules.ConclusionsOur findings support the view that MKL1 contributes to the expression of caveolar proteins in healthy kidneys and orchestrates the induction of tubular caveolar proteins in renal injury.
Highlights
Caveolae are membrane invaginations measuring 50–100 nm
SDPR/CAVIN2 appeared to be preferentially localized to endothelial cells whereas PRKCDBP/CAVIN3 was preferentially localized to the vascular media
In the proximal tubular segments adjacent to sclerosing glomeruli, we could detect staining for caveolin-1/CAV1, caveolin-2/CAV2, SDPR/ CAVIN2 and PRKCDBP/CAVIN3 (Fig. 1m-p and Table 2)
Summary
Caveolae are membrane invaginations measuring 50–100 nm. These organelles, composed of caveolin and cavin proteins, are important for cellular signaling and survival. The classical view that randomly surviving cells dedifferentiate and repopulate the injured tubules has recently been challenged by data favouring progenitor or stem cells as primary regenerative actors [1] Regardless of this debate, we and others have described remarkable changes of tubular phenotype in response to injury and during regeneration, and that the parietal epithelial cells (PEC) of Bowman’s capsule normally express the markers of these regenerating cells [2]. These tubular phenotypic alterations play an ill-defined role in disease resolution or progression. Given that caveolin1/CAV1 and caveolae have been proposed to influence signaling, transport and disease processes in the kidney [8,9,10] it is important to understand the mechanisms that underlie induction of caveolin-1/CAV1 and potentially other caveolar proteins in kidney disease
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