Abstract
In the last 30 years, a worldwide increase in chronic kidney disease was reported in agricultural regions and hence was named Chronic Interstitial Nephritis in Agricultural Communities (CINAC). The exact cause and molecular disease mechanism underlying CINAC remain unknown. However, increasing evidence points towards exposure to agrochemicals (e.g. pesticides) as a causal factor. Recently, in kidney biopsies from CINAC-patients, we discovered a lysosomal lesion in proximal tubular cells (PTCs). Moreover, we discovered the same lesion in transplant patients treated with nephrotoxic immunosuppressive calcineurin inhibitors (CNIs), leading to the paradigm that CINAC indeed is caused by a toxin. Yet, the nature of the toxin, as well as cell biological mechanisms involved remain elusive. Therefore, we will focus our investigation on human renal biopsies of CINAC- and transplant-patients, who will be subjected to single nucleus RNA sequencing to generate a molecular profile of the renal cells. With this information, we will conduct reverse toxicogenomics to identify possible causal toxins. Next, gene expression analysis, complemented with functional analyses in primary human renal cell cultures as well as in rodents, allows an extensive mechanistic investigation supplementing our in silico analyses. Finally, molecular markers obtained from these efforts will be visualized in human samples in their histopathological context to link our molecular findings translational diagnosis.
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