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. Author manuscript; available in PMC: 2021 Dec 1.
Published in final edited form as: Kidney Int. 2020 Aug 1;98(6):1589–1604. doi: 10.1016/j.kint.2020.06.041

Figure 10. Pathophysiology of ADTKD-REN.

Figure 10.

(A) Wild type preprorenin is cotranslationally translocated into the ER. The signal sequence is cleaved during translocation, and nascent prorenin is glycosylated. Prorenin then transits through the ER-Golgi Intermediate Compartment (ERGIC), which monitors proper protein folding and detects aberrant protein forms. In the Golgi apparatus prorenin is both sorted to clear vesicles and constitutively secreted to proto-granules, where it is proteolytically processed to renin, which is later subjected to regulated secretion. (B) Mutations in the signal peptide prevent translocation across the ER membrane and the preprorenin is aberrantly located in the cytoplasm. This results in clinical renin deficiency and ER stress in renin producing cells. Mutations in the mature renin lead to retention of mutated protein in ER. This initiates ER stress similar to that seen in UMOD mutations and uromodulin retention in ADTKD-UMOD. Mutations in the prosegment introduce structural changes affecting protein biosynthesis, folding and travel along the secretory pathway causing clinical renin deficiency and potentially also cellular toxicity leading to chronic kidney disease.