Shear Forces and the Vulnerability of the Podocyte

Podocyte detachment is a critical step in the progression of glomerular disease. What does it take to detach the podocyte from its footing on the glomerular basement membrane? In this issue of JASN, a new model is presented to address this question.¹ Fuhrmann et al. ask us to think about the dynamic flow forces acting on the podocyte. Consider Newton's second law of motion:

$$\mathrm{F}=\mathrm{m}·\mathrm{a}$$

where F is the sum of forces on the podocyte, m is podocyte mass, and a is its acceleration. Under normal circumstances, the podocyte is stationary, so acceleration is 0 and the sum of forces is 0. Tensile forces hold the podocyte in place (shear forces=tensile forces). Podocyte detachment when it occurs reflects an imbalance in forces (shear forces>tensile forces). The force to displace or detach the podocyte is shear stress arising from noncompressible laminar flow through the filtration slit. It has units of force (dynes/cm² or Pascal Pa) and depends primarily on the fluid flow rate and its viscosity.

This group has previously estimated shear forces on the podocyte with a simple geometric model of overall glomerular dimensions.² Here, they approach the problem in a new way using a technique from fluid mechanics called computational fluid dynamics, which is an established engineering method used to study flow in confined spaces, large or small. The technique simulates the patterns of fluid movement in a defined three-dimensional space through iterative calculations that start with the basic laws of fluid movement embodied in the Navier–Stokes equations, physical dimensions, driving forces, and fluid characteristics. Because of the nonlinearities and complex geometries, direct solutions of the equations for flow or shear force are not possible. Iterative, computationally intensive calculations are needed, and specialized, established software is used to yield estimates of the critical variables. Computational fluid dynamics has been applied extensively to study fluid flow in the vasculature where it has proven useful for mechanistic studies of vascular injury and for practical problems such as the design of stents.³ The technique has not previously been applied to study fluid flow in the glomerulus.

The authors build on decades of research on the dynamics of glomerular filtration. They work with standard rat parameters—single nephron glomerular filtration rate of 30 nl/min and filtration pressure difference of 17 mm Hg—and use their established geometric measures of the glomerular basement membrane and slit diaphragm. The starting point for the model is the physiological Deen model of Starling forces, largely validated by the experimental work of Brenner and colleagues as well as others. The other starting point is the pioneering work of Farquhar who established the critical role of the basement membrane in size and charge selectivity hindering the entry of large molecules.⁴ The slit diaphragm acts as the final barrier. The authors of the present report take these findings as established and make the simplifying assumption that the fluid crossing the slit diaphragm is protein free, a modest oversimplification but one that seems to have minimal effect.

The current study produces a high-resolution spatial model of the filtration process. The focus is on the slit diaphragm and the space right beyond it. It predicts that the slit diaphragm behaves like a nozzle—producing high-velocity fluid flow through the slit and shear forces on the wall of podocyte foot processes. Estimates for the shear force are surprisingly high, 10- to 50-fold higher than previous estimates, and much higher than estimates for shear forces on vascular endothelium.^3,5 The hypothesis that emerges is that high shear forces are an important contributor to the vulnerability of the podocyte.

What are we to make of these new findings? Computational modeling has become somewhat easier, thanks to the availability of proprietary software and the fact that tools like Chat generative pretrained transformer can assist with the programming. However, as more complex virtual models emerge, we still need to scrutinize them for practical value. Does this model give us useful and testable experimental predictions?

The shear forces on the podocyte are currently not directly measurable, at least in situ, given the miniscule scale and spatial constraints—but methods are getting closer, and it is possible to consider experimental validation of these findings. This 3D model is spatial, and new tools, such as fluorescent polarization microscopy⁶ and improved proteomic methods,⁷ permit high-resolution study of spatial patterns of cellular injury. So, here are some questions—a short list of hard questions—some new, some old—where these findings may help move us forward.

A gradient of injury along the glomerular capillary? Shear forces are expected to vary along the glomerular capillary, greater at the afferent end, reduced at the efferent end as filtration pressure equilibrium is approached. Do the patterns of injury fit with this expectation? To identify sites early versus late in the capillary loop would require either careful image reconstruction techniques⁸ or an optical marker—but with a tool to identify early and late sites, this hypothesis could be put to a direct test.

Short of detachment, do shear forces damage the membranes of podocytes? What are the points of cell injury? The spatial model predicts shear stress will be greatest on the walls of the foot process, not on the cell body, not on the foot plate. In fact, moderate levels of shear forces may be beneficial to epithelial cells,⁹ but damaging effects on the podocyte have been demonstrated in cultured cells² and single kidneys.¹⁰ The spatial distribution of injury could provide an informative test of the role of shear forces, and documenting localized changes in calcium or presence of any of the proteins known to play a role in membrane repair, for example, the endosomal sorting complexes required for transport proteins,¹¹ could serve to document localized membrane damage.

What comes first? Is shear force a target for early intervention? Most of the expanding array of drugs shown to slow the progression of CKD share the common property of initially lowering GFR, suggesting benefit may be in part tied to reduction in shear force. Furthermore, by and large, documented benefit is only clear cut in patients with established disease and proteinuria. Can a focus on early molecular markers of high shear force, for example, in shed podocytes, lead to better understanding of the earliest factors that cause disease and better strategies to target early disease?

This intriguing model raises good questions. We hope it will provoke studies to get good answers.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/E978.

Funding

None.

Author Contributions

Conceptualization: Josephine P. Briggs, Mark A. Knepper.

Writing – original draft: Josephine P. Briggs, Mark A. Knepper.