Glomerular Biomechanical Stress and Lipid Mediators during Cellular Changes Leading to Chronic Kidney Disease

Abstract

Hyperfiltration is an important underlying cause of glomerular dysfunction associated with several systemic and intrinsic glomerular conditions leading to chronic kidney disease (CKD). These include obesity, diabetes, hypertension, focal segmental glomerulosclerosis (FSGS), congenital abnormalities and reduced renal mass (low nephron number). Hyperfiltration-associated biomechanical forces directly impact the cell membrane, generating tensile and fluid flow shear stresses in multiple segments of the nephron. Ongoing research suggests these biomechanical forces as the initial mediators of hyperfiltration-induced deterioration of podocyte structure and function leading to their detachment and irreplaceable loss from the glomerular filtration barrier. Membrane lipid-derived polyunsaturated fatty acids (PUFA) and their metabolites are potent transducers of biomechanical stress from the cell surface to intracellular compartments. Omega-6 and ω-3 long-chain PUFA from membrane phospholipids generate many versatile and autacoid oxylipins that modulate pro-inflammatory as well as anti-inflammatory autocrine and paracrine signaling. We advance the idea that lipid signaling molecules, related enzymes, metabolites and receptors are not just mediators of cellular stress but also potential targets for developing novel interventions. With the growing emphasis on lifestyle changes for wellness, dietary fatty acids are potential adjunct-therapeutics to minimize/treat hyperfiltration-induced progressive glomerular damage and CKD.

Generally-healthy individuals with aberrant bowel movement frequencies show enrichment for microbially-derived blood metabolites associated with reduced kidney function

“…The Omega-6/Omega-3 ratio, in particular, may be related to higher levels of pro-inflammatory Omega-6 lipids and lower levels of anti-inflammatory Omega-3 lipids in the diet [65]. A diet enriched in processed foods and animal products is known to drive increased risk of chronic kidney disease [66,67]. The directionality of these associations point towards lower BMFs being associated with higher systemic inflammation, which may lead to increased chronic disease risk potentially through compromised gut epithelia.…”

Adipose tissue as risk factor for kidney disease

“…The RAAS activation leads to sodium retention in tubules, contributing to systemic and intra-renal hypertension and impacting renal blood flow, perfusion, and intra-glomerular hypertension [56]. Consequently, related stress is imposed on renal vasculature glomerular cells and podocytes, and eventually, there is a decline in kidney function [57]. Alternatively, insulin resistance plays a vital role in kidney damage development.…”

The Intersection of Genetic Factors, Aberrant Nutrient Metabolism and Oxidative Stress in the Progression of Cardiometabolic Disease

“…Sustained or progressive damage can lead to CKD. On the other hand, FAs might indirectly influence CKD outcomes via the production of numerous lipid mediators [204]. Arachidonic acid-derived products, such as leukotrienes, can promote kidney damage through leukocyte recruitment [205].…”

“…A summary of the influence of nutrient metabolism on CKD is presented in Figure 3 and a summary of the in vitro, in vivo and clinical findings on CKD are summarized in Table 3. Lipid-derived mediators Exaggerates or protects against CKD depending on mediator and context [204]; [205]; [206];…”