Mutations in the ubiquitin ligase scaffold protein Cullin 3 (CUL3) cause the disease Familial Hyperkalemic Hypertension (FHHt). We recently reported that in the kidney, aberrant mutant CUL3 (CUL3-Δ9) activity lowers abundances of CUL3-Δ9 and Kelch-Like 3, the CUL3 substrate adaptor for WNK4, and that this is mechanistically important. However, whether CUL3-Δ9 exerts additional effects on other targets that may alter renal function is unclear. Here, we sought to determine (i) whether CUL3-Δ9 expression can rescue the phenotype of renal tubule-specific Cul3 knockout mice and (ii) whether CUL3-Δ9 expression affects other CUL3 substrates. Using an inducible renal tubule-specific system, we studied two CUL3-Δ9-expressing mouse models, Cul3-knockout (Cul3-/-/Δ9) and Cul3-heterozygotes background (Cul3+/-/Δ9, FHHt model). The effects of CUL3-Δ9 in these mice were compared with Cul3-/- and Cul3+/- mice. Similar to Cul3-/- mice, Cul3-/-/Δ9 mice displayed polyuria with loss of AQP2 and collecting duct injury; proximal tubule injury also occurred. CUL3-Δ9 did not promote degradation of two CUL3 targets that accumulate in Cul3-/- kidney: high molecular weight cyclin E, and NQO1 (a surrogate for the CUL3-Kelch-like ECH-associated protein 1 (KEAP1) substrate NRF2). Since CUL3-Δ9 expression cannot rescue the Cul3-/- phenotype our data suggest CUL3-Δ9 cannot normally functioning ubiquitin ligase complexes. In Cul3+/-/Δ9 mice, KEAP1 abundance did not differ but NQO1 abundance was higher, suggesting adaptor sequestration by CUL3-Δ9 in vivo. Together, our results provide evidence that in kidney, CUL3-Δ9 completely lacks normal activity and can trap CUL3 substrate adaptors in inactive complexes.