Novel molecular mechanisms of organ crosstalk and kidney injury from inhaled silica.

The growing burden of kidney disease in the U.S. and worldwide is attributed in part to non-traditional risk factors. The potential public health impact is staggering, with over 850 million people currently affected by chronic kidney disease (CKD) alone and global costs for CKD projected to top $400 billion by 2027. Exposure to airborne hazards is one prominent but poorly understood CKD risk. Air pollution has been convincingly linked to adverse kidney health outcomes, including incident CKD, CKD progression, end stage kidney disease, albuminuria, and hospitalization for acute kidney injury. Occupational exposure to silica dust has been linked to renal-related mortality and inhalation of silica dust from kilns, silica-rich crops, ash, and other sources is implicated in the complex pathogenesis of CKD of unknown etiology (CKDu), an emerging disease now reported in over 35 tropical countries and manifest primarily as chronic tubulointerstitial injury. The mechanisms by which inhaled toxins such as respirable silica contribute to remote renal tubule injury and subsequent kidney disease, particularly in communities experiencing high heat exposures, are unclear. This is a critical knowledge gap and highlights the need for rigorous preclinical studies. We propose that kidney cells are injured indirectly by endogenous soluble nephrotoxic mediators released into the bloodstream from damaged lung, noting that lung- kidney communication has already been implicated in glomerulopathies. Our long-term goal is to identify molecular mechanisms of interorgan communication that mediate remote organ injury after environmental exposures that impact human health. The short-term goals are to document kidney injury using complementary sensitive functional assays and to determine if circulating microRNAs (MiRs) are altered early after silica inhalation at time points likely to reflect injury-modulating pathways. Our hypothesis is that silica exposure alters renal function in part by inducing circulating MiR capable of engaging cognate mRNAs in critical kidney cell compartments, and that concurrent heat stress, a common co-exposure, exacerbates this response. Our transdisciplinary team will test this hypothesis in two complementary but independent Aims, the feasibility of which is supported by preliminary data: Aim 1: Quantify early changes in kidney function and cell transcriptomes induced by exposure to inhaled silica, with and without concurrent simulated heat wave co-exposure, and Aim 2: Identify circulating MiRs as candidate mediators of interorgan signaling, using prediction and prioritization algorithms in both aims to gain novel insight into molecular mechanisms. Ultimately these proof-of-principle studies aim to establish regulation of kidney mRNA and/or circulating MiRs as plausible molecular events involved in lung-kidney crosstalk and kidney injury early after inhalational exposures. Our results should stimulate new ideas to prevent and treat exposure-related remote organ injury, particularly for individuals facing multiple CKD risks. Project Number: 1R21ES038368-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Environmental Health Sciences (NIEHS) | Principal Investigator: MARY FOSTER (+1 co-PI) | Institution: DUKE UNIVERSITY, DURHAM, NC | Award Amount: $444,125 | Activity Code: R21 | Study Section: Environmental Determinants of Disease Study Section [EDD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11302984