Fig. 1: The DNA damage-induced KLF6-RPB1 pathway causes a transcriptional switch to sustain tubular dedifferentiation and promote failed recovery and fibrosis.

In the murine model of Balkan nephropathy, the naturally occurring toxic aristolochic acid I (AAI) is systemically injected and primarily taken up into proximal tubule cells by basolateral organic anion transporters OAT1 and OAT3. This is followed by DNA adduct formation, DNA injury response, and direct cytotoxic effects of AAI to cause cell injury and reactive upregulation of KLF6 expression. KLF6 facilitates failed injury recovery by inhibiting catabolism of branched chain amino acids (BCAA)⁴ or, as shown now⁷, by inducing the expression of RNA polymerase II (RNAPII) subunit 2 (Polr2a/RPB1), causing a possible persistent stalling of RNAPII. This seems to reprogram transcription and thereby trap proximal tubular cells with DNA damage in a dedifferentiated state that enhances fibrosis. Suggesting potential for translation, individuals with diabetic kidney disease also show an association between kidney DNA damage and RPB1 expression. See text for more details.