The collagen IVα345 (Col-IVα345) scaffold, the major constituent of the glomerular basement membrane (GBM), is a critical component of the kidney glomerular filtration barrier. In chronic kidney disease, affecting hundreds of millions of people worldwide, over two thousand genetic variants occur in the COL4A3, COL4A4, and COL4A5 genes that encode the α3, α4, and α5 chains of the Col-IVα345 scaffold. The chains are the autoantigens in Goodpasture’s (GP) autoimmune disease, mutated in Alport syndrome, and dysfunctional in diabetic nephropathy (DN). The rationale development of therapy hinges on gaining new understandings of pathogenic mechanisms. GP disease, a renal pulmonary disorder, continues to serve as the vanguard for unlocking these medical mysteries. Among our discoveries are: a) the crystal structure of the NC1 hexamer of the α345 collagen IV scaffold, b) discovery of the primordial chloride pressure and its constraint against neoepitope formation in Goodpasture’s disease3, c) discovery of functionality of the α345 NC1 hexamer in the assembly of the GBM as an ultrafilter of proteins, d) development of the collagen triple-helix mapping tool, e) capacity of NC1 domain to home in the assembly of basement membranes, and f) detrimental effect of high glucose on the BM modifying enzymes. These published discoveries, together with substantial amount of unpublished pilot data, provide the framework for four specific aims. Our overarching hypothesis is: Col-IVα345 tethers macromolecules forming supramolecular complexes, perturbation of which, in genetic and acquired disorders, cause glomerulopathies. The achievement of the aims will yield new insights into the etiology of GP, the structure and assembly of collagen IV scaffolds and binding partners, and the molecular mechanisms of underlying DN. This knowledge is of fundamental importance for the rationale design of therapies that target the primary cause disease.