Mechanisms of Diabetic Nephropathy in Humans and Experimental Animals

Several major advances over the last years have increased our understanding of the pathogenesis of diabetic kidney disease (DKD), thanks in large part to the utility of experimental animal models. Pathologically, DKD is characterized by glomerular basement membrane thickening, mesangial matrix expansion, glomerulosclerosis, and tubulointerstitial fibrosis. These changes correlate clinically with the development of albuminuria and hypertension and a decline in glomerular filtration rate (GFR). While a unifying hypothesis for diabetic pathogenesis has been difficult to prove, various metabolic, hemodynamic, and inflammatory pathways have been shown to redundantly activate molecular and cellular pathways of injury. Hyperglycemia alters glucose metabolism in renal cells causing it to utilize alternative pathways and is associated with mitochondrial dysfunction. Meanwhile, nonenzymatic glycation, oxidative stress, and protein kinase C signaling contribute to further glucotoxicity. Further, the renin–angiotensin–aldosterone system (RAAS) has been demonstrated to be central to the early hemodynamic changes in the glomerulus including hyperfiltration and intraglomerular hypertension. This explains the protective role of agents that intercept the RAAS (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers) and the new findings on the efficacy of novel mineralocorticoid receptor antagonists in preventing DKD progression. However, recently the success of the sodium–glucose cotransporter inhibitors in delaying kidney injury brought to light hypotheses on the role of tubuloglomerular feedback in the development of hyperfiltration. All the different pathways activated in the diabetic kidney converge to activate pathways for fibrosis, heralding the final stages of DKD. By further elucidating the pathophysiology of DKD, newer and more effective therapies will be on the horizon.